Enriching neuron-specific extracellular vesicles, and their use in identifying and treating subjects with neurodegenerative disorders

Abstract

Methods and materials for identifying and using neuron-specific extracellular vesicles are provided herein. For example, provided herein are methods and materials for identifying neuron-specific extracellular vesicles and assessing the presence and / or amount of disease biomarkers associated with the identified extracellular vesicles.

Description

[0001] Attorney Docket No.07039-2255WO1 2022-307 ENRICHING NEURON-SPECIFIC EXTRACELLULAR VESICLES, AND THEIR USE IN IDENTIFYING AND TREATING SUBJECTS WITH NEURODEGENERATIVE DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of priority from U.S. Provisional Application Serial No.63 / 538,355, filed September 14, 2023. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application. STATEMENT OF FEDERALLY SPONSORED RESEARCH This invention was made with government support under AG054199 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD This document relates to methods and materials for identifying and using neuron- specific extracellular vesicles. For example, this document relates to methods and materials for identifying neuron-specific extracellular vesicles and assessing the presence and / or amount of disease biomarkers associated with the identified extracellular vesicles. BACKGROUND Extracellular vesicles (EVs) are cell-derived small membranous vesicles that can carry a variety of molecules, including lipids, nucleic acids, and proteins (You and Ikezu, Neurobiol Dis 130:104512, 2019). EV cargos can be dynamically altered by pathophysiological conditions, such that EVs can reflect disease-specific signatures. Thus, EVs are a promising tool for discovering biomarkers of various disorders, including neurological / neurodegenerative disorders. Past attempts to enrich putative neuron-derived EVs (NDEVs) from patient- derived biopsies or biofluids have relied on immunocapturing the presumed neural marker L1 cell adhesion molecule (L1CAM) (Gomes and Witwer, J Extracell Biol 1:e35, 2022) or neural cell adhesion molecule 1 (NCAM1) (Mustapic et al., Front Neurosci Attorney Docket No.07039-2255WO1 2022-307 11:278, 2017), followed by characterization of the NDEV contents as a pathological reflection of the central nervous system (CNS). However, the reliability of using such markers of brain neuronal EVs has been questioned (see, e.g., Norman et al., Nat Methods 18:631-634, 2021). SUMMARY This document is based, at least in part, on the identification of ATPase Na+ / K+Transporting Subunit Alpha 3 (ATP1A3) as an abundant neuron-specific EV marker (see, e.g., You et al., J Extracell Vesicles 11:e12183, 2022), and on the discovery that ATP1A3 is specific to NDEVs and is a promising target for NDEV pulldown from accessible biofluids for monitoring of neurodegenerative disorders such as Alzheimer’s disease (AD). Provided herein are methods and materials for identifying mammals as having, or as being likely to have, disorders such as AD, as well as methods for treating mammals identified as having, or as being likely to have, AD. As demonstrated herein, ATP1A3, a transmembrane ion pump, was identified as a NDEV marker in an unbiased proteomics study. EVs derived from human induced pluripotent stem cell-derived excitatory neurons (iNeurons), human brain, and cerebrospinal fluid (CSF) were isolated and evaluated by immuno-transmission electron microscopy and single particle-interferometric reflectance imaging sensor (SP-IRIS) analysis, which revealed that ATP1A3 is more frequently co-localized with tetraspanins on the EV surface at the single particle level, as compared to NCAM1 or L1CAM. Immunoblotting demonstrated enrichment of ATP1A3 in EVs from both brain and CSF samples, as compared to NCAM1 and L1CAM. Further, label-free mass spectrometry demonstrated greater enrichment of neuron-specific proteins, including SNAP25, SYT1, and CAMK2A, in ATP1A3+brain EVs as compared to NCAM1+or L1CAM+brain EVs. Proteins in ATP1A3+brain-EVs also were significantly associated with myelin sheath, synapse, neurodegenerative diseases, and neuronal cell type, suggesting that ATP1A3- associated EVs reflect the neuron origin in the brain. Finally, the presence of AD marker proteins, including amyloid-? peptides 1-40 (A?40) and 1-42 (A?42), total tau, ptau at T181 (P-tau181), and the neuronal protein SNAP25, was observed in ATP1A3+CSF-EVs Attorney Docket No.07039-2255WO1 2022-307 using high-sensitivity digital ELISA (Simoa), demonstrating that ATP1A3-associated EVs are a promising source of AD biomarkers. Thus, the results described herein demonstrated that ATP1A3 is a target for enriching NDEVs from human samples, providing a new avenue for observing molecular changes associated with neurological diseases in the CNS. Moreover, having the ability to reliably identify mammals as having AD or other CNS disorders can allow those mammals to be properly identified and treated in an effective and reliable manner. In one aspect, this document features a method for identifying a mammal as having, or as being likely to have, AD. The method can include, or consist essentially of, obtaining EVs derived from a biological sample from the mammal; determining that the EVs are ATP1A3+; and assessing the level of one or more biomarkers associated with AD in the EVs and ascertaining that the EVs have an elevated level of the one or more biomarkers; thereby identifying the mammal as having, or as being likely to have, AD. The mammal can be a human. The biological sample can be a plasma sample, a CSF sample, a brain tissue sample, or a brain lysate. The determining can include contacting the EVs with an anti-ATP1A3 antibody. The anti-ATP1A3 antibody can include a first label. The assessing can include contacting the EVs with one or more antibodies against the one or more biomarkers. The one or more antibodies each can include a label that is different from the first label. The one or more biomarkers can include one or more of ??40, A?42, total tau, P-tau181, and SNAP25. In another aspect, this document features a method for treating a mammal identified as having, or as being likely to have, AD. The method can include, or consist essentially of, (a) identifying the mammal as having, or as being likely to have, AD by (i) obtaining EVs derived from a biological sample from the mammal, (ii) determining that the EVs are ATP1A3+, and (iii) assessing the level of one or more biomarkers associated with AD in the EVs and ascertaining that the EVs have an elevated level of the one or more biomarkers; and (b) administering to the mammal one or more therapeutic agents for treating the AD. The mammal can be a human. The biological sample can be a plasma sample, a CSF sample, a brain tissue sample, or a brain lysate. The determining can include contacting the EVs with an anti-ATP1A3 antibody. The anti-ATP1A3 antibody Attorney Docket No.07039-2255WO1 2022-307 can include a first label. The assessing can include contacting the EVs with one or more antibodies against the one or more biomarkers. The one or more antibodies each can have a label that is different from the first label. The one or more biomarkers can include one or more of A?40, A?42, total tau, P-tau181, and SNAP25. The method can include administering a therapeutic agent selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab. The method can include administering a cholinesterase inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine. The method can further include monitoring the mammal for progression of the AD. In another aspect, this document features a method for treating a mammal identified as having, or as being likely to have, AD, wherein the method includes, or consists essentially of, administering, to a mammal identified as having plasma- or CSF- derived EVs that (a) are ATP1A3+and (b) have an elevated level of one or more biomarkers associated with AD, one or more therapeutic agents for treating the AD. The mammal can be human. The method can include administering a therapeutic agent selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab. The method can include administering a cholinesterase inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine. The method can further include monitoring the mammal for progression of the AD. In still another aspect, this document features a method that includes, or consists essentially of, providing a solid substrate having a surface with discrete areas to which one or more EV capture molecules are attached; contacting the surface with a sample containing one or more EVs, such that the one or more EVs bind to the one or more EV capture molecules; immunostaining the bound EVs with one or more labeled antibodies, wherein each of the one or more labeled antibodies is targeted to a biomarker for a selected cell type or disorder, and wherein each of the one or more labeled antibodies has a detectable label; and imaging the immunostained EVs to detect the presence of each the detectable label. The solid substrate can be a glass slide or a glass coverslip. The one or more EV capture molecules can include a capture antibody. The capture antibody can is an anti-CD9 antibody, an anti-CD63 antibody, or an anti-CD81 antibody. The capture Attorney Docket No.07039-2255WO1 2022-307 antibody can be an anti-ATP1A3 antibody. The capture antibody can be an antibody against a marker for oligodendrocytes, a marker for astrocytes, or a marker for microglia. The capture antibody can be an antibody against a marker for oligodendrocytes, and the marker for oligodendrocytes can be LAMP2, FTH1, or PLP1. The capture antibody can be an antibody against a marker for astrocytes, and the marker for astrocytes can be LRP1, ITGA6, or EAAT1. The capture antibody can be an antibody against a marker for microglia, and the marker for microglia can be ITGAM, LCP1, or P2RY12. The one or more labeled antibodies can include an antibody against a marker for AD. The marker for AD can be selected from the group consisting of A?40, A?42, total tau, P-tau181, and SNAP25. The one or more labeled antibodies can include an antibody against a marker for Parkinson’s disease, an antibody against a marker for amyotrophic lateral sclerosis (ALS), or an antibody against a marker for frontotemporal dementia (FTD). The one or more labeled antibodies can include an antibody against a marker for Parkinson’s disease, and the marker for Parkinson’s disease can be alpha-synuclein. The one or more labeled antibodies can include an antibody against a marker for ALS or FTD, and the marker for ALS or FTD can be Tau or TDP-43. The imaging can include one or more of Simoa, SP- IRIS, dSTORM, single-molecule localization microscopy (SMLM), proximal ligation amplification (PLA), and Nanoflow Cytometry (NanoFCM). In another aspect, this document features a method for identifying a mammal as having, or as being likely to have, AD, where the method includes, or consists essentially of, determining that EVs derived from a biological sample from the mammal and determined to contain ATP1A3 have an elevated level of one or more biomarkers associated with AD, thereby identifying the mammal as having, or as being likely to have, AD. The mammal can be a human. The biological sample can be a plasma sample, a CSF sample, a brain tissue sample, or a brain lysate. The determining can include contacting the EVs with one or more antibodies against the one or more biomarkers. The one or more antibodies each can have a different label. The biomarkers can include one or more of A?40, A?42, total tau, P-tau181, and SNAP25. In another aspect, this document features a method for treating a mammal identified as having, or as being likely to have, AD, where the method includes, or Attorney Docket No.07039-2255WO1 2022-307 consists essentially of, (a) identifying the mammal as having, or as being likely to have, AD by determining that EVs derived from a biological sample from the mammal and determined to contain ATP1A3 have an elevated level of one or more biomarkers associated with AD, and (b) administering, to the mammal, one or more therapeutic agents for treating the AD. The mammal can be a human. The biological sample can be a plasma sample, a CSF sample, a brain tissue sample, or a brain lysate. The determining can include contacting the EVs with one or more antibodies against the one or more biomarkers. The one or more antibodies each can have a different label. The biomarkers can include one or more of A?40, A?42, total tau, P-tau181, and SNAP25. The method can include administering a therapeutic agent selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab. The method can include administering a cholinesterase inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine. The method can further include monitoring the mammal for progression of the AD. In another aspect, this document features a method for identifying a mammal as having, or as being likely to have, a neurologic disorder, where the method includes, or consists essentially of, determining that ATPase Na+ / K+Transporting Subunit Alpha 3- positive extracellular vesicles (ATP1A3+EVs) obtained from a biological sample of the mammal have (a) the presence of an elevated level of a biomarker elevated in ATP1A3+EVs of the neurologic disorder or (b) the presence of a reduced level of a biomarker reduced in ATP1A3+EVs of the neurologic disorder, thereby identifying the mammal as having, or as being likely to have, the neurologic disorder. The mammal can be a human. The biological sample can be a plasma sample, a cerebrospinal fluid (CSF) sample, a brain tissue sample, or a brain lysate. The ATP1A3+EVs can have been isolated from the biological sample using an anti-ATP1A3 antibody. The anti-ATP1A3 antibody can have a first label. The method can include determining that the ATP1A3+EVs have the presence of the elevated level of the biomarker elevated in ATP1A3+EVs of the neurologic disorder. The presence of the elevated level of the biomarker elevated in ATP1A3+EVs of the neurologic disorder can be determined using an antibody against the biomarker elevated in ATP1A3+EVs of the neurologic disorder. The antibody against the biomarker Attorney Docket No.07039-2255WO1 2022-307 elevated in ATP1A3+EVs of the neurologic disorder can have a label that is different from the first label. The neurologic disorder can be AD. The biomarker elevated in ATP1A3+EVs of AD can be selected from the group consisting of A?40, A?42, total tau, P-tau181, T217 (P-tau217), T231 (P-tau231), neurofilament light chain (NEFL), and SNAP25. The neurologic disorder can be selected from the group consisting of Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, and brain tumors. For example, the neurologic disorder can be Parkinson’s disease, and the biomarker elevated in ATP1A3+EVs of the Parkinson’s disease can be selected from the group consisting of alpha-synuclein, oligomeric alpha-synuclein, phosphorylated alpha- synuclein, and PARK7. The neurologic disorder can be ALS, and the biomarker elevated in ATP1A3+EVs of the ALS can be selected from the group consisting of Tau, TDP-43, and SOD1. The neurologic disorder can be FTD, and the biomarker elevated in ATP1A3+EVs of the FTD can be selected from the group consisting of Tau, TDP-43, and phosphorylated TDP-43. The neurologic disorder can be multiple sclerosis, and the biomarker elevated in ATP1A3+EVs of the multiple sclerosis can be selected from the group consisting of CCL26, CCL22, and CXCL10. The neurologic disorder can be chronic traumatic encephalopathy, and the biomarker elevated in ATP1A3+EVs of the chronic traumatic encephalopathy can be selected from the group consisting of Tau, phosphorylated tau, and NEFL. The neurologic disorder can be Huntington’s disease, and the biomarker elevated in ATP1A3+EVs of the Huntington’s disease can be HTT. The neurologic disorder can be prion disease, and the biomarker elevated in ATP1A3+EVs of the prion disease can be selected from the group consisting of Tau, phosphorylated tau, and NEFL. The neurologic disorder can be viral encephalitis, and the biomarker elevated in ATP1A3+EVs of the viral encephalitis can be selected from the group consisting of IFNG, IL1B, and TNF. The neurologic disorder can be cerebrovascular disease, and the biomarker elevated in ATP1A3+EVs of the cerebrovascular disease can be selected from the group consisting of APOE, SAA1, and VCAM1. The neurologic disorder can be a brain tumor, and the biomarker elevated in ATP1A3+EVs of the brain tumor can be selected from the group consisting of GFAP, S100B, and VGF. The method can include Attorney Docket No.07039-2255WO1 2022-307 determining that the ATP1A3+EVs have the presence of the reduced level of the biomarker reduced in ATP1A3+EVs of the neurologic disorder. The presence of the reduced level of the biomarker reduced in ATP1A3+EVs of the neurologic disorder can be determined using an antibody against the biomarker reduced in ATP1A3+EVs of the neurologic disorder. The antibody against the biomarker reduced in ATP1A3+EVs of the neurologic disorder can have a label that is different from the first label. The neurologic disorder can be AD. The biomarker reduced in ATP1A3+EVs of the AD can be selected from the group consisting of ACHE, FABP3, and TREM2. In another aspect, this document features a method for treating a mammal having, or likely having, a neurologic disorder, where the method includes, or consists essentially of, administering a treatment agent for the neurologic disorder to a mammal identified as having ATPase Na+ / K+Transporting Subunit Alpha 3-positive extracellular vesicles (ATP1A3+EVs) that have (a) the presence of an elevated level of a biomarker elevated in ATP1A3+EVs of the neurologic disorder or (b) the presence of a reduced level of a biomarker reduced in ATP1A3+EVs of the neurologic disorder. The mammal can be a human. The ATP1A3+EVs can be plasma ATP1A3+EVs, cerebrospinal fluid (CSF) ATP1A3+EVs, brain tissue ATP1A3+EVs, or brain lysate ATP1A3+EVs. The mammal can have been identified as having the ATP1A3+EVs that have the presence of the elevated level of the biomarker elevated in ATP1A3+EVs of the neurologic disorder. The presence of the elevated level of the biomarker elevated in ATP1A3+EVs of the neurologic disorder can have been determined using an antibody against the biomarker elevated in ATP1A3+EVs of the neurologic disorder. The neurologic disorder can be AD. The biomarker elevated in ATP1A3+EVs of the AD can be selected from the group consisting of A?40, A?42, total tau, P-tau181, and SNAP25. The treatment agent for the AD can be selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab. The neurologic disorder can be selected from the group consisting of Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, and brain tumors. For example, the neurologic disorder can be Parkinson’s disease, the biomarker elevated in ATP1A3+EVs of the Parkinson’s disease Attorney Docket No.07039-2255WO1 2022-307 can be selected from the group consisting of alpha-synuclein, oligomeric alpha-synuclein, phosphorylated alpha-synuclein, and PARK7, and the treatment agent for the Parkinson’s disease can be selected from the group consisting of pramipexole (Mirapex), ropinirole (Requip), rotigotine (Neupro), and Amantadine. The neurologic disorder can be ALS, the biomarker elevated in ATP1A3+EVs of the ALS can be selected from the group consisting of Tau, TDP-43, and SOD1, and the treatment agent for the ALS can be selected from the group consisting of Qalsody, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta. The neurologic disorder can be FTD, the biomarker elevated in ATP1A3+EVs of the FTD can be selected from the group consisting of Tau, TDP-43 and phosphorylated TDP-43, and the treatment agent for the FTD can be selected from the group consisting of olanzapine (Zyprexa), quetiapine (Seroquel), and trazodone. The neurologic disorder can be multiple sclerosis, the biomarker elevated in ATP1A3+EVs of the multiple sclerosis can be selected from the group consisting of CCL26, CCL22, and CXCL10, and the treatment agent for the multiple sclerosis can be selected from the group consisting of Glatiramer acetate, Ofatumumab, Siponimod, and Cladribine. The neurologic disorder can be chronic traumatic encephalopathy, the biomarker elevated in ATP1A3+EVs of the chronic traumatic encephalopathy can be selected from the group consisting of Tau, phosphorylated tau, and NEFL, and the treatment agent for the chronic traumatic encephalopathy can be selected from the group consisting of Lexapro (escitalopram), Celexa (citalopram), Sinemet (carbidopa / levodopa), Aricept (donepezil), and Namenda (memantine). The neurologic disorder can be Huntington’s disease, the biomarker elevated in ATP1A3+EVs of the Huntington’s disease can be HTT, and the treatment agent for the Huntington’s disease can be selected from the group consisting of Tetrabenazine (Xenazine), deutetrabenazine (Austedo), valbenazine (Ingrezza), and Haloperidol (Haldol). The neurologic disorder can be prion disease, the biomarker elevated in ATP1A3+EVs of the prion disease can be selected from the group consisting of Tau, phosphorylated tau, and NEFL, and the treatment agent for the prion disease can be selected from the group consisting of Quinacrine, Pentosan polysulfate (PPS), and PRN100. The neurologic disorder can be viral encephalitis, the biomarker elevated in ATP1A3+EVs of the viral encephalitis can be selected from the group consisting of Attorney Docket No.07039-2255WO1 2022-307 IFNG, IL1B, and TNF, and the treatment agent for the viral encephalitis can be selected from the group consisting of cyclovir (Zovirax, Sitavig), Ganciclovir, and Foscarnet (Foscavir). The neurologic disorder can be cerebrovascular disease, the biomarker elevated in ATP1A3+EVs of the cerebrovascular disease can be selected from the group consisting of APOE, SAA1, and VCAM1, and the treatment agent for the cerebrovascular disease can be selected from the group consisting of Apixaban (Eliquis), Dabigatran (Pradaxa), Edoxaban (Savaysa), Heparin (various), Rivaroxaban (Xarelto), and Warfarin (Coumadin). The neurologic disorder can be a brain tumor, the biomarker elevated in ATP1A3+EVs of the brain tumor can be selected from the group consisting of GFAP, S100B, and VGF, and the treatment agent for the brain tumor can be selected from the group consisting of Afinitor Disperz (Everolimus), Avastin (Bevacizumab), Belzutifan, and BiCNU (Carmustine). The mammal can have been identified as having the ATP1A3+EVs that have the presence of the reduced level of the biomarker reduced in ATP1A3+EVs of the neurologic disorder. The presence of the reduced level of the biomarker reduced in ATP1A3+EVs of the neurologic disorder can have been determined using an antibody against the biomarker reduced in ATP1A3+EVs of the neurologic disorder. The neurologic disorder can be AD. The biomarker reduced in ATP1A3+EVs of the AD can be selected from the group consisting of ACHE, FABP3, and TREM2. The treatment agent for the AD can be selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and Attorney Docket No.07039-2255WO1 2022-307 advantages of the invention will be apparent from the description and drawings, and from the claims. DESCRIPTION OF DRAWINGS FIGS.1A-1C: The expression pattern of ATP1A3 protein in the brain. FIG.1A, Representative image of ATP1A3 staining in the adult mouse whole brain. Scale bar, 1 mm. FIG.1B, Representative images showing ATP1A3 co-stained with MAP2, GFAP, and IBA1 in the dentate gyrus (DG) and CA1 regions of WT and APPNL-G-Fmice, and fluorescence intensity profiles for the indicated line scans (marked in white in the “Zoom in” images) of ATP1A3 and cell type markers. Scale bars, 100 ?m and 25 ?m. FIG.1C, Representative images showing ATP1A3 co-stained with MAP2, GFAP, and IBA1 in the dentate gyrus (DG) and CA1 regions of healthy individuals and AD patients, and fluorescence intensity profiles for the indicated line scans (marked in white in the “Zoom in” images) of ATP1A3 and cell type markers. Scale bars, 100 ?m and 25 ?m. FIG.2: RNA expression of neuron-specific EV marker candidates (ATP1A3, NCAM1, and L1CAM) in human tissues and single cell types of the brain. Normalized RNA expression levels (nTPM) for molecules of interest are shown for the different tissues and single brain-cell types. Data were accessed from the Human Protein Atlas dataset. The ATP1A3 gene shows more restricted expression in brain and is enriched in neurons compared to NCAM1 and L1CAM, which are widely expressed in other tissues or glia cells. FIGS.3A-3F: ATP1A3 is a neuron-specific EV marker candidate beside NCAM1 and L1CAM, and is associated with EVs in human brain tissues and biofluids at a single-particle level. FIG.3A, Experimental design for evaluating whether NDEV marker candidates (ATP1A3, NCAM1, and L1CAM) are associated with EVs. iNeuron, human induced pluripotent stem cell derived excitatory neuron; UC, ultracentrifugation; SU-GC, sucrose gradient centrifugation; SEC, size exclusion chromatography. FIG.3B, Transmission electron micrograph (TEM) showing immunogold labeling of EVs isolated from iNeuron, brain, CSF and plasma stained with anti-CD9 antibody (10 nm), and anti- ATP1A3, anti-NCAM1, and anti-L1CAM antibodies (5 nm). Scale bar, 100 nm. FIG. Attorney Docket No.07039-2255WO1 2022-307 3C, Representative fluorescent images of iNeuron-EVs detected by fluorescent- conjugated antibodies (red: ATP1A3-AF647, NCAM1-AF647, or L1CAM-AF647; blue: CD9 / 81C / 63-AF488) on EXOVIEW™ chip CD63 capture spots. Circles in the magnified images show co-stained particles with tetraspanins. Scale bars, 25 ?m and 5 ?m. FIG. 3D, Percentages of ATP1A3, NCAM1, and L1CAM fluorescent particle counts relative to total particles in iNeuron derived EVs (n = 2 biological replicates) on EXOVIEW™ chip tetraspanins capture spots. FIG.3E, Representative fluorescent images of brain- and CSF-EVs detected by fluorescent-conjugated antibodies (green: ATP1A3-AF555, red: NCAM1-AF647 or L1CAM-AF647; blue: CD9 / 81 / 63-AF488) on EXOVIEW™ chip CD9 capture spots. Circles in the magnified images show co-stained particles with tetraspanins. Scale bars, 25 ?m and 5 ?m. FIG.3F, Percentages of ATP1A3, NCAM1, and L1CAM fluorescent particle counts relative to total particles in brain- (n = 2) and CSF- (n = 2) derived EVs on EXOVIEW™ chip tetraspanins capture spots. FIGS.4A-4D: Purity assessment of NGN2-induced human iNeurons. FIG.4A, Neuron differentiation from induced pluripotent stem cells (iPSCs). MAP2, a neuron- specific marker; GFAP, an astrocyte-specific marker. Scale bar, 100 ?m. FIG.4B, Percentage of MAP2+cells in iNeuron culture. A total of 578 cells from two independent cultures were counted. FIG.4C, Abundance of neuron- and astrocyte-specific proteins in iNeuron culture according to a quantitative label-free mass spectrometry dataset described elsewhere (You et al., J Extracell Vesicles 11(1):e12183, 2022). The iBAQ (intensity- based absolute quantification) values of proteins including neuronal markers (MAP2, MAPT, SYT1 (synaptotagmin 1), SYP (synaptophysin), and SYN1 (synapsin 1)) and astrocytic markers (GFAP and S100?) are plotted. N = 3. Data are presented as mean ± SEM. FIG.4D, Immuno-staining of ATP1A3, NCAM1, and L1CAM expression in iNeurons. Scale bar, 5 ?m. FIGS.5A-5D: Neuronal EV markers expression in iNeuron-, brain- and CSF-EV samples using the SP-IRIS analysis on the EXOVIEW™ R100 system. FIG.5A, Schematics of single EV staining using EXOVIEW™ chip. FIG.5B, Heatmap showing the total fluorescent particle counts of iNeuron-EVs (n = 2) on a single capture spot with Attorney Docket No.07039-2255WO1 2022-307 isotype IgG as negative control. FIG.5C, Heatmap showing the total fluorescent particle counts of brain-EVs (n = 2) and CSF-EVs (n = 2) on a single capture spot with isotype IgG as negative control. FIG.5D, Colocalization analysis of neuron-specific EV marker candidates with tetraspanins in brain (n=2) and CSF (n=2) derived EVs. Error bars represent one SEM. FIGS.6A-6F: Comparative analysis of NDEV candidate marker (ATP1A3, NCAM1, and L1CAM) expression in EVs by super-resolution microscopy. FIG.6A, Schematic showing the staining protocol of ATP1A3 and NCAM1 for EVs. FIG.6B, Representative super-resolution microscopy images showing the expression of ATP1A3 and NCAM1 in pan-tetraspanins (CD9 / 81 / 63) positive EVs at a single-particle level. Scale bar, 100 nm. FIG.6C, Pie charts showing the heterogenous EV population with ATP1A3 and NCAM1 in different EV preparations. Particles with a diameter less than 200 nm were quantified. FIG.6D, Schematic showing the staining protocol of ATP1A3 and L1CAM for EVs. FIG.6E, Representative super-resolution microscopy images showing the expression of ATP1A3 and L1CAM in pan-tetraspanins (CD9 / 81 / 63) positive EVs at a single-particle level. Scale bar, 100 nm. FIG.6F, Pie charts showing the heterogenous EV population with ATP1A3 and L1CAM in different EV preparations. Particles with a diameter less than 200 nm were quantified. FIGS.7A-7B: Western blot analysis of neuronal EV marker proteins in human brain tissues. FIG.7A, Brain lysates and associated EVs isolated from healthy controls (n = 3) were immunoblotted for neuron EV markers (ATP1A3, NCAM1, and L1CAM), common EV markers (CD9 and CD81), and non-EV markers including Golgi apparatus marker GM130, mitochondrial protein cytochrome C (CytoC), and histone protein H2A. Equivalent proteins from brain lysates and EVs were loaded as indicated in the total staining gel. FIG.7B, Statistical analysis showed significant enrichment of ATP1A3 in brain-associated EVs as compared to brain lysates. Data are presented as mean ± SEM. Significance was determined using paired t-test between brain lysates and EVs. *P < 0.05. FIGS.8A-8B: Western blot images of neuronal EV marker proteins in human biofluids. CSF (FIG.8A) and plasma (FIG.8B) and associated EVs were immunoblotted Attorney Docket No.07039-2255WO1 2022-307 for neuron EV markers (ATP1A3, NCAM1, and L1CAM) and common EV markers (ANXA2, CD9, and CD81). Equivalent proteins were loaded for biofluid samples and EVs. The experiment was repeated 3 time with similar results. FIGS.9A-9C: Proteinase protection assay. FIG.9A, Schematic overview of EV integrity analysis after Proteinase K treatment. FIG.9B, Western blot analysis of neuronal EV markers (ATP1A3, NCAM1, and L1CAM) after Proteinase K treatment of brain-EV (n = 3), showing the external expression of these molecules in EVs as compared to the common EV surface marker CD81, potential internal protein Tau, and GAPDH. FIG.9C, Relative expression levels normalized to GAPDH. Data are presented as mean ± SEM. Significance was determined using paired t-test between PK treated and non-treated EVs. *P < 0.05, **P < 0.01. FIGS.10A-10G: ATP1A3+EVs immunoprecipitated from human brain tissues displays higher neuronal cell-type specificity. FIG.10A, Workflow for characterizing ATP1A3+, NCAM1+, and L1CAM+EVs immunoprecipitated from brain. FIG.10B, Western blot images of 5% total EVs (Input), supernatant (S.P), and immunoprecipitated EVs (A, ATP1A3; L, L1CAM; N, NCAM1) isolated from control brains (n = 3) and probed for neuron and glia markers. Equivalent proteins from brain-EVs were used for immunocapturing ATP1A3, L1CAM, and NCAM1. SYP, synaptophysin. FIG.10C, Principal component analysis (PCA). The EV proteomes of total brain-EVs and immunoprecipitated EVs were measured in triplicate and classified. FIG.10D, Venn diagram showing the number of proteins differentially identified in total, ATP1A3+, L1CAM+, and NCAM1+brain-EVs by proteomics (n = 3 per group). FIG.10E, Gene ranking dotplot showing differentially expressed proteins in ATP1A3+brain-EVs compared to NCAM1+and L1CAM+brain-EVs. FIG.10F, Gene ontology, pathway, and cell type enrichment analysis of total identified proteins in ATP1A3+brain-EVs. FIG. 10G, Heatmaps showing the expression level of proteins associated with KEGG pathway term Alzheimer’s disease and Cell Atlas term Neuronal cell type within each immunoprecipitated EV sample. FIGS.11A-11C: Brain-derived EV proteome. FIG.11A, Unsupervised hierarchical clustering of the total identified brain-EV proteins (n = 3 for each group). FIG. Attorney Docket No.07039-2255WO1 2022-307 11B, Bubble plots showing the enriched pathways related to GO_Cellular Component, KEGG pathway and Cell Atlas terms in identified proteins from NCAM1+brain-EVs (left panel) and L1CAM+brain-EVs (right panel). FIG.11C, Bubble plots showing the enriched pathways related to GO_Cellular Component, KEGG pathway and Cell Atlas terms in unique proteins from ATP1A3+brain-EVs (left panel) and NCAM1+brain-EVs (right panel). FIGS.12A-12J: ATP1A3+EV analysis in human cerebrospinal fluid and plasma. FIG.12A, Schematic showing workflow for characterizing ATP1A3+EVs immunoprecipitated from CSF. FIG.12B, Simoa quantification of AD related neuropathogenic proteins (A?42, A?40, T-tau, P-tau181, and SNAP25) in ATP1A3+CSF-EVs from healthy controls (n = 3) and AD (n = 3). Data are presented by box and whisker plot which shows the median and the 25th to 75th percentiles. FIG.12C, ??42 / A?40 ratio in CSF, total CSF-EVs, and ATP1A3 IP CSF-EVs samples in the AD group. FIG.12D, Schematic showing workflow explaining single particle analysis of ??+population in ATP1A3+plasma-EVs to distinguish Alzheimer’s disease from healthy controls (CTL) and mild cognitive impairment (MCI). FIG.12E, Representative super- resolution microscopy images showing plasma-derived A?+ATP1A3+single EVs among control, MCI, and AD groups (green: FITC-CD9 / 81 / 63, red: Alexa flour 555-ATP1A3, grey: Alexa flour 647-A? (clone 4G8)). Scale bar, 100 nm. FIG.12F, Percentage of A?+population in ATP1A3+plasma-EVs in control, MCI, and AD groups (n = 10 / group). FIG.12G, Correlation of A?+population in ATP1A3+plasma-EVs with clinical Braak stage, Mini-Mental State Exam (MMSE), and Dementia Rating Scale (DRS) (Pedraza et al., Arch Clin Neuropsychol 25:347-358, 2010) scores in combined control (n = 7), MCI (n = 10), and AD (n = 10) samples. The dashed line indicates 95% confidence band of the best-fit line. Pearson correlation coefficients are shown. FIG.12H, Quantification of ??42 / A?40 level in total plasma samples from CTL (n = 9), MCI (n = 10), and AD (n = 10). FIGS.12I-12J, Receiver-operating characteristics (ROC) curves indicating the performance of the A?+population in ATP1A3+plasma-EVs, plasma A?40, A?42, ??42 / A?40 ratio, and T-tau to distinguish AD from CTL (FIG.12I) and AD from MCI Attorney Docket No.07039-2255WO1 2022-307 (FIG.12J). T-tau, total tau; AUC, area under the curve; CI, confidence interval; ns, no significance; *P < 0.05, **P < 0.01, ***P < 0.001. FIGS.13A-13B: Validation of immunoprecipitation efficiency from total CSF- EVs using anti-ATP1A3, anti-NCAM1, and anti-L1CAM antibodies. FIG.13A, Representative western blot images of 5% total CSF-EVs (Input), supernatant (S.P), and CSF-EVs immunoprecipitated for ATP1A3, NCAM1, and L1CAM and probed for EV marker CD9. Equivalent proteins from total CSF-EVs were initiated for immunocapturing ATP1A3, NCAM1, and L1CAM. FIG.13B, Comparable expression levels of ATP1A3, L1CAM, and NCAM1 in individual immunoprecipitated CSF-EV samples (n = 4), detected by commercial ELISA kits. Significance was determined by Ordinary one-way ANOVA with Tukey’s post hoc test. Data are presented as mean ± SEM. **P < 0.01; n.s, no significance. LOD, limit of detection. FIGS.14A-14B: Validation of immunoprecipitation efficiency from total plasma- EVs using anti-ATP1A3, anti-NCAM1, and anti-L1CAM antibodies. FIG.14A, Representative western blot images of 5% total plasma-EVs (Input), supernatant (S.P), and plasma-EVs immunoprecipitated for ATP1A3, NCAM1, and L1CAM and probed for EV markers ANXA2 and CD9. Equivalent proteins from total plasma-EVs were initiated for immunocapturing ATP1A3, NCAM1, and L1CAM. FIG.14B, Comparable expression levels of ATP1A3, L1CAM, and NCAM1 in individual immunoprecipitated plasma-EV samples (n = 4), detected by commercial ELISA kits. Significance was determined by unpaired t- test. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01; n.s, no significance. LOD, limit of detection. FIGS.15A-15B: Characterization of extracellular vesicles from total CSF-EVs and CSF-EVs immunoprecipitated by anti-ATP1A3, anti-NCAM1, and anti-L1CAM antibodies, respectively. FIG.15A, Representation of size distribution of total and immunoprecipitated EVs from CSF by nanoparticle tracking analysis. FIG.15B, Statistical analysis of particle size mode, mean and number among total CSF-EVs, ATP1A3+CSF-EVs, NCAM1+CSF-EVs, and L1CAM+CSF-EVs (n=4). Data are presented as mean ± SEM. n.s., no significance; *P < 0.05, **P < 0.01, ****P < 0.0001 as determined by student’s t-test. Attorney Docket No.07039-2255WO1 2022-307 FIGS.16A-16C: Single particle analysis of plasma-EVs from healthy controls, MCI, and AD patients by super-resolution microscopy. FIG.16A, Plasma-derived EV particle size distribution from Nanoimager among control, MCI, and AD groups. The left panels show large fields of EV clusters and the right panels show magnified fields. Scale bar, 5 ?m and 1 ?m. FIG.16B, Representative clustering analysis of plasma-EVs isolated from healthy controls, MCI, and AD patients showing A? distribution in ATP1A3+Pan- tetraspanins+single particles by super-resolution microscopy. FIG.16C, Percentages of heterogenous EV populations in plasma derived EVs among control, MCI, and AD groups (n = 10 per group). Particles with a diameter less than 400 nm were quantified. Data are presented as mean ± SEM. FIGS.17A-17D: Single particle analysis of NCAM1+and L1CAM+plasma-EVs from healthy controls and AD patients by super-resolution microscopy. FIG.17A, Representative clustering analysis of plasma-EVs isolated from healthy controls and AD patients showing A? distribution in NCAM1+Pan-tetraspanins+single particles by super- resolution microscopy. The left panels show large fields of EV clusters and the right panels show magnified fields. Scale bars, 5 ?m and 1 ?m. FIG.17B, Percentages of heterogenous EV populations in plasma derived EVs among control and AD groups (n = 5 per group). Particles with a diameter less than 400 nm were quantified. Data are presented as mean ± SEM. FIG.17C, Representative clustering analysis of plasma-EVs isolated from healthy controls and AD patients showing A? distribution in L1CAM+Pan- tetraspanins+single particles by super-resolution microscopy. Left panels show large fields of EV clusters and right panels show magnified fields. Scale bars, 5 ?m and 1 ?m. FIG.17D, Percentages of heterogenous EV populations in plasma-derived EVs among control and AD groups (n = 5 per group). Particles with a diameter less than 400 nm were quantified. Data are presented as mean ± SEM. FIG.18: Simoa quantification of AD related neuropathogenic proteins (A?42, ??40, and T-tau) in total plasma samples from healthy controls (n = 9), MCI (n = 10), and AD (n = 10). Data are presented as mean ± SEM. Significance was determined using Ordinary one-way ANOVA with Tukey’s post hoc test or Kruskal-Wallis nonparametric Attorney Docket No.07039-2255WO1 2022-307 ANOVA with Dunn’s post hoc test after normality tests of Shapiro-Wilk. n.s, no significance. FIG.19: Venn diagram showing the identified proteins from ATP1A3+plasma- EVs in control and AD groups, confirming the applicability of directly immunoprecipitating ATP1A3+EVs from plasma samples. Human plasma samples (3 AD and 3 control (CTL) cases, 500 ?L each) were tested for immunoprecipitation of ATP1A3+by anti-ATP1A3 antibody, followed by data independent acquisition (DIA)- based liquid chromatography mass-spectrometry (LC-MS) for proteomic profiling. A total of 1721 plasma proteins were identified (1680 proteins in CTL, and 1699 proteins in AD) for at least one out of three samples. FIG.20: Expression of protein of interest from DIA-MS results from the identified proteins of FIG.19. FIG.21: List of 120 targets in CNS disease panel. FIG.22: Workflow showing incorporation of the NUcleic acid Linked Immuno- Sandwich Assay (NULISA). A pair of antibodies for each target – (a) a capture antibody conjugated with partially double-stranded DNA containing a poly-A tail and a target- specific molecular identifier (TMI) and (b) a detection antibody conjugated with another partially double-stranded DNA containing a biotin group and a matching target-specific barcode (TMI) is pooled into a multiplex panel. Incubation of antibodies with a sample containing the target antigen results in the formation of an immunocomplex (Inset #1). The formed immunocomplexes are subsequently captured by addition of paramagnetic oligo-dT beads via dT-polyA hybridization (Inset #2), and the sample matrix and unbound detection antibodies are removed by washing (Inset #3). As dT-polyA binding is sensitive to salt concentration, the immunocomplexes are then released into a low-salt buffer (Inset #4). After removal of the dT beads, a second set of paramagnetic beads coated with streptavidin is introduced for a second capture of the immunocomplexes in the solid phase (Inset #5). Subsequent washes remove any unbound capture antibodies leaving only intact immunocomplexes on the beads. Then, a ligation reaction mix containing T4 DNA ligase and a specific DNA ligator sequence along with a sample- specific molecular identifier (SMI) is added, allowing the ligation of the proximal ends of Attorney Docket No.07039-2255WO1 2022-307 the DNA attached to the paired antibodies and, thus, generating a DNA reporter molecule containing unique pairs of TMIs (Inset #6) and a SMI. The amount of the DNA reporter can then be quantified by next-generation sequencing (NGS). FIG.23: Protein detectability results. FIG.24: Venn diagram showing the unique targets detected in total EVs and ATP1A3+EVs. FIG.25: List of proteins of interest that were detected among different samples using the NULISA assay. FIG.26A: Graph comparing protein expression levels (indicated by protein NPQ values) between ATP1A3+EV and total EV. FIG.26B: Graph comparing protein expression levels (indicated by protein NPQ values) between ATP1A3+EV and neat plasma. FIG.27: Graphs plotting ACHE, FABP3, and TREM2 levels detected in neat plasma, total plasma EVs, and ATP1A3+plasma-EVs from AD and control patients. P values are provided for each comparison. Significant p value < 0.05. DETAILED DESCRIPTION EVs are membrane-bound particles released by the majority of human cells, including cells within the CNS (Heijnen et al., Blood 1999, 94:3791-3799; and Kowal et al., Curr Opin Cell Biol 2014, 29:116-125). EVs can contain DNA, messenger RNA (mRNA), non-coding RNA, and proteins, which can be released into the microenvironment and are thought to play key roles in cell-to-cell communication between neurons, glia, and endothelial cells for complex functions including moderation of the blood-brain barrier (Li et al., RNA Biol 2013, 10:1333-1344; Proia et al., Int J Mol Med 2008, 21:63-67; and Schiera et al., J Cell Mol Med 2007, 11:1384-1394). EVs in peripheral blood provide a lipid-membrane bound container of DNA, RNA, and proteins that are protected from circulating degradation enzymes, and therefore may provide a snapshot of the microenvironment in specific organ systems shortly before a peripheral blood sample is taken. In the studies described herein, ATP1A3 was found to be a NDEV marker in populations of EVs derived from human plasma, iNeurons, brain, and CSF. Attorney Docket No.07039-2255WO1 2022-307 Further, AD marker proteins (e.g., A?40, A?42, total tau, P-tau181, and SNAP25) were observed in ATP1A3+CSF-EVs using Simoa, indicating that such EVs can be used to identify mammals (e.g., humans) as having, or being likely to have, AD. Moreover, methods analogous to those described herein can be used to identify and isolate EVs derived from specific populations of neural cells (e.g., astrocytes, oligodendrocytes, and microglia), and / or to identify markers of other neurologic or neurodegenerative disorders (e.g., Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, and brain tumors). In some cases, this document provides methods and materials for identifying and / or treating mammals (e.g., humans) who have, or who are at an increased likelihood of having, AD. In some cases, the methods and materials provided herein can be used to determine that a mammal (e.g., a human) has, or is likely to have, AD rather than MCI. Any appropriate mammal can be identified as having, or being likely to have, AD using the methods and materials described herein. For example, humans and other primates such as monkeys having can be identified as having AD as described herein. In some cases, laboratory animals such as mice, rats, or rabbits can be identified as having AD as described herein. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) AD by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated or reduced) levels of one or more AD markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, AD include, without limitation, A?40, A?42, total tau, P-tau181, P-tau217, P- tau231, NEFL, SNAP25, ACHE, FABP3, and TREM2. For example, a mammal (e.g., a human) can be identified as having (or as being likely to have) AD by detecting the presence of ATP1A3+NDEVs having elevated levels of one or more of A?40, A?42, total tau, P-tau181, P-tau217, P-tau231, NEFL, and SNAP25. For example, a mammal (e.g., a human) can be identified as having (or as being likely to have) AD by detecting the presence of ATP1A3+NDEVs having reduced levels of one or more of ACHE, FABP3, and TREM2. Attorney Docket No.07039-2255WO1 2022-307 In some cases, this document provides methods and materials for identifying and / or treating mammals (e.g., humans) who have, or who are at an increased likelihood of having, a neurologic disorder such as, without limitation, Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or a brain tumor. Any appropriate mammal can be identified as having, or being likely to have, Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or a brain tumor using the methods and materials described herein. For example, humans and other primates such as monkeys having can be identified as having Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or a brain tumor as described herein. In some cases, laboratory animals such as mice, rats, or rabbits can be identified as having Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or a brain tumor as described herein. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) Parkinson’s disease by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more Parkinson’s disease markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, Parkinson’s disease include, without limitation, alpha- synuclein, oligomeric alpha-synuclein, phosphorylated alpha-synuclein, and PARK7. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) ALS by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more ALS markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, ALS include, without limitation, Tau, TDP-43, and SOD1. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) FTD by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more FTD markers. Examples of markers that can be Attorney Docket No.07039-2255WO1 2022-307 evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, FTD include, without limitation, Tau, TDP-43, and phosphorylated TDP-43. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) multiple sclerosis by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more multiple sclerosis markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, multiple sclerosis include, without limitation, CCL26, CCL22, and CXCL10. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) chronic traumatic encephalopathy by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more chronic traumatic encephalopathy markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, chronic traumatic encephalopathy include, without limitation, Tau, phosphorylated tau, and NEFL. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) Huntington’s disease by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more Huntington’s disease markers. An example of a marker that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, Huntington’s disease includes, without limitation, HTT. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) prion disease by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more prion disease markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, prion disease include, without limitation, Tau, phosphorylated tau, and NEFL. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) viral encephalitis by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more viral encephalitis markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as Attorney Docket No.07039-2255WO1 2022-307 having, or being likely to have, viral encephalitis include, without limitation, IFNG, IL1B, and TNF. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) cerebrovascular disease by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more cerebrovascular disease markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, cerebrovascular disease include, without limitation, APOE, SAA1, and VCAM1. As described herein, a mammal (e.g., a human) can be identified as having (or as being likely to have) a brain tumor by detecting the presence of ATP1A3+NDEVs having altered (e.g., elevated) levels of one or more brain tumor markers. Examples of markers that can be evaluated and used to classify a mammal (e.g., a human) as having, or being likely to have, a brain tumor include, without limitation, GFAP, S100B, and VGF. EVs can be obtained from any appropriate biological sample (e.g., blood, plasma, serum, CSF, brain tissue, or iNeurons) from a mammal (e.g., a human). Moreover, any appropriate method can be used to obtain EVs from a biological sample. Suitable methods for obtaining EVs include, without limitation, density gradient ultracentrifugation, microfluidics, centrifugal filtration, size exclusion chromatography, affinity purification, and precipitation. In some cases, ATP1A3+EVs (also referred to as NDEVs) can be isolated from a population of EVs derived from, for example, plasma or CSF. ATP1A3+EVs can be isolated from a population of EVs using any appropriate method. For example, immunoprecipitation of EVs with an anti-ATP1A3 antibody can be used to isolate ATP1A3+EVs, as described herein. Suitable anti-ATP1A3 antibodies include, for example, ATP1A3 monoclonal antibody XVIF9-G10, which is commercially available from ThermoFisher Scientific (Waltham, MA; Cat# MA3915). Any appropriate method can be used to determine if a mammal (e.g., a human) has NDEVs with an elevated level of one or more markers of AD or another neurologic or neurodegenerative disorder (e.g., Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, Attorney Docket No.07039-2255WO1 2022-307 cerebrovascular disease, or brain tumor). The term “elevated level” or “increased level” as used herein with respect to a marker level refers to a level of the marker present within or otherwise associated with EVs that is greater (e.g., at least 5, 10, 25, 35, 45, 50, 55, 65, 75, 80, 90, or 100 or more percent greater) than the median level of that marker within or otherwise associated with control EVs from a mammal that does not have a neurologic or neurodegenerative disorder such as AD, Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or brain tumor (e.g., from a neurologically healthy mammal). The term “reduced level” or “decreased level” as used herein with respect to a marker level refers to a level of the marker present within or otherwise associated with EVs that is less (e.g., at least 5, 10, 25, 35, 45, 50, 55, 65, 75, 80, 90, or 100 percent less) than the median level of that marker within or otherwise associated with control EVs from a mammal that does not have a neurologic or neurodegenerative disorder such as AD, Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or brain tumor (e.g., from a neurologically healthy mammal). Appropriate methods for identifying EVs as having an elevated or reduced level of one or more markers as described herein include, without limitation, Simoa, SP-IRIS (ExoView), dSTORM, SMLM, PLA, and NanoFCM. In some cases, EVs can be simultaneously co-stained with an antibody for ATP1A3 and antibodies for one or more AD markers, where the antibodies are coupled to different labels. Such co-staining can allow the identification of ATP1A3+EVs and the assessment of AD marker levels in a single step. Co-stained EVs can be visualized by, for example, dSTORM in order to identify EVs that are ATP1A3+, and to determine whether the ATP1A3+EVs express an elevated or reduced level of the tested AD markers. In some cases, EVs can be simultaneously co-stained with an antibody for ATP1A3 and antibodies for one or more markers of a neurologic or neurodegenerative disorder (e.g., Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or brain tumor), where the antibodies are coupled to different labels. Such co- Attorney Docket No.07039-2255WO1 2022-307 staining can allow the identification of ATP1A3+EVs and the assessment of neurologic / neurodegenerative disease marker levels in a single step. Co-stained EVs can be visualized by, for example, dSTORM in order to identify EVs that are ATP1A3+, and to determine whether the ATP1A3+ EVs express an elevated or reduced level of the tested markers. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the AD markers described herein, the mammal can be classified as having, or as being likely to have, AD. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., two, three, four, five, or more than five) markers selected from A?40, A?42, total tau, P-tau181, P-tau217, P-tau231, NEFL, and SNAP25 can be classified as having, or as being likely to have, AD. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., two, three, four, five, or more than five) markers selected from ??40, A?42, total tau, P-tau181, P-tau217, P-tau231, NEFL, and SNAP25 can be classified as not having, or as not being likely to have, AD. Once a mammal (e.g., a human) is identified as having NDEVs with a reduced level of one or more of the AD markers described herein, the mammal can be classified as having, or as being likely to have, AD. For example, a human identified as having NDEVs with reduced levels of one or more (e.g., one, two, or three) markers selected from ACHE, FABP3, and TREM2 can be classified as having, or as being likely to have, AD. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit reduced levels of the one or more (e.g., one, two, or three) markers selected from ACHE, FABP3, and TREM2 can be classified as not having, or as not being likely to have, AD. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the Parkinson’s disease markers described herein, the mammal can be classified as having, or as being likely to have, Parkinson’s disease. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., two, three, or four) markers selected from alpha-synuclein, oligomeric alpha-synuclein, phosphorylated alpha-synuclein, and PARK7 can be classified as having, or as being Attorney Docket No.07039-2255WO1 2022-307 likely to have, Parkinson’s disease. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., two, three, or four) markers selected from alpha-synuclein, oligomeric alpha-synuclein, phosphorylated alpha-synuclein, and PARK7 can be classified as not having, or as not being likely to have, Parkinson’s disease. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the ALS markers described herein, the mammal can be classified as having, or as being likely to have, ALS. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., one, two, or three) markers selected from Tau, TDP-43, and SOD1 can be classified as having, or as being likely to have, ALS. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., one, two, or three) markers selected from Tau, TDP-43, and SOD1 can be classified as not having, or as not being likely to have, ALS. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the FTD markers described herein, the mammal can be classified as having, or as being likely to have, FTD. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., one, two, or three) markers selected from Tau, TDP-43, and phosphorylated TDP-43 can be classified as having, or as being likely to have, FTD. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., one, two, or three) markers selected from Tau, TDP-43, and phosphorylated TDP-43 can be classified as not having, or as not being likely to have, FTD. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the multiple sclerosis markers described herein, the mammal can be classified as having, or as being likely to have, multiple sclerosis. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., one, two, or three) markers selected from CCL26, CCL22, and CXCL10 can be classified as having, or as being likely to have, multiple sclerosis. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., Attorney Docket No.07039-2255WO1 2022-307 one, two, or three) markers selected from CCL26, CCL22, and CXCL10 can be classified as not having, or as not being likely to have, multiple sclerosis. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the chronic traumatic encephalopathy markers described herein, the mammal can be classified as having, or as being likely to have, chronic traumatic encephalopathy. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., one, two, or three) markers selected from Tau, phosphorylated tau, and NEFL can be classified as having, or as being likely to have, chronic traumatic encephalopathy. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., one, two, or three) markers selected from Tau, phosphorylated tau, and NEFL can be classified as not having, or as not being likely to have, chronic traumatic encephalopathy. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of the Huntington’s disease marker described herein, the mammal can be classified as having, or as being likely to have, Huntington’s disease. For example, a human identified as having NDEVs with elevated levels of HTT can be classified as having, or as being likely to have, Huntington’s disease. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of HTT can be classified as not having, or as not being likely to have, Huntington’s disease. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the prion disease markers described herein, the mammal can be classified as having, or as being likely to have, prion disease. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., one, two, or three) markers selected from Tau, phosphorylated tau, and NEFL can be classified as having, or as being likely to have, prion disease. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., one, two, or three) markers selected from Tau, phosphorylated tau, and NEFL can be classified as not having, or as not being likely to have, prion disease. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the viral encephalitis markers described herein, the mammal can Attorney Docket No.07039-2255WO1 2022-307 be classified as having, or as being likely to have, viral encephalitis. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., one, two, or three) markers selected from IFNG, IL1B, and TNF can be classified as having, or as being likely to have, viral encephalitis. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., one, two, or three) markers selected from IFNG, IL1B, and TNF can be classified as not having, or as not being likely to have, viral encephalitis. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the cerebrovascular disease markers described herein, the mammal can be classified as having, or as being likely to have, cerebrovascular disease. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., one, two, or three) markers selected from APOE, SAA1, and VCAM1 can be classified as having, or as being likely to have, cerebrovascular disease. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., one, two, or three) markers selected from APOE, SAA1, and VCAM1 can be classified as not having, or as not being likely to have, cerebrovascular disease. Once a mammal (e.g., a human) is identified as having NDEVs with an elevated level of one or more of the brain tumor markers described herein, the mammal can be classified as having, or as being likely to have, a brain tumor. For example, a human identified as having NDEVs with elevated levels of one or more (e.g., one, two, or three) markers selected from GFAP, S100B, and VGF can be classified as having, or as being likely to have, a brain tumor. In some cases, a mammal (e.g., a human) identified as having NDEVs that do not exhibit elevated levels of the one or more (e.g., one, two, or three) markers selected from GFAP, S100B, and VGF can be classified as not having, or as not being likely to have, a brain tumor. This document also provides methods and materials for selecting a mammal (e.g., a human) for treatment for AD or another neurologic or neurodegenerative disorder (e.g., Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or brain Attorney Docket No.07039-2255WO1 2022-307 tumor), where the mammal has been identified as having, or as being likely to have, AD or another neurologic / neurodegenerative disorder using the methods described herein. In addition, this document provides methods and materials for treating a mammal (e.g., a human) identified as having, or as being likely to have, AD or another neurologic / neurodegenerative disease using the methods described herein. Any appropriate mammal identified as having, or as being likely to have, AD can be treated by, for example, administering one or more therapeutic agents. For example, one or more cholinesterase inhibitors (e.g., donepezil (Aricept, Adlarity), galantamine (Razadyne), or rivastigmine transdermal patch (Exelon)), one or more agents that prevent amyloid plaques in the brain from clumping (e.g., lecanemab (Leqembi)), one or more agents that target and reduce amyloid plaques and tau proteins (e.g., donanemab), memantine (Namenda), aducanumab (Aduhelm), or any combination thereof, can be administered to a mammal identified as having, or as being likely to have, AD. Having the ability to identify mammals who have, or are likely to have, AD can allow clinicians and patients to proceed with treatment options that may alleviate effects of AD (e.g., by improving memory or improving symptoms related to behavior, such as agitation or depression) and / or may delay the progression of AD. Any appropriate mammal identified as having, or as being likely to have, Parkinson’s disease as described herein can be treated by, for example, administering one or more therapeutic agents. For example, pramipexole (Mirapex), ropinirole (Requip), rotigotine (Neupro), Amantadine, or any combination thereof can be administered to a mammal identified as having, or as being likely to have, Parkinson’s disease as described herein. Having the ability to identify mammals who have, or are likely to have, Parkinson’s disease as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of Parkinson’s disease and / or may delay the progression of Parkinson’s disease. Any appropriate mammal identified as having, or as being likely to have, ALS as described herein can be treated by, for example, administering one or more therapeutic agents. For example, Qalsody, Radicava, Rilutek, Tiglutik, Exservan, Nuedexta, or any combination thereof can be administered to a mammal identified as having, or as being Attorney Docket No.07039-2255WO1 2022-307 likely to have, ALS as described herein. Having the ability to identify mammals who have, or are likely to have, ALS as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of ALS and / or may delay the progression of ALS. Any appropriate mammal identified as having, or as being likely to have, FTD as described herein can be treated by, for example, administering one or more therapeutic agents. For example, olanzapine (Zyprexa), quetiapine (Seroquel), trazodone, or any combination thereof can be administered to a mammal identified as having, or as being likely to have, FTD as described herein. Having the ability to identify mammals who have, or are likely to have, FTD as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of FTD and / or may delay the progression of FTD. Any appropriate mammal identified as having, or as being likely to have, multiple sclerosis as described herein can be treated by, for example, administering one or more therapeutic agents. For example, Glatiramer acetate, Ofatumumab, Siponimod, Cladribine, or any combination thereof can be administered to a mammal identified as having, or as being likely to have, multiple sclerosis as described herein. Having the ability to identify mammals who have, or are likely to have, multiple sclerosis as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of multiple sclerosis and / or may delay the progression of multiple sclerosis. Any appropriate mammal identified as having, or as being likely to have, chronic traumatic encephalopathy as described herein can be treated by, for example, administering one or more therapeutic agents. For example, Lexapro (escitalopram), Celexa (citalopram), Sinemet (carbidopa / levodopa), Aricept (donepezil), Namenda (memantine), or any combination thereof can be administered to a mammal identified as having, or as being likely to have, chronic traumatic encephalopathy as described herein. Having the ability to identify mammals who have, or are likely to have, chronic traumatic encephalopathy as described herein can allow clinicians and patients to proceed with Attorney Docket No.07039-2255WO1 2022-307 treatment options that may alleviate effects of chronic traumatic encephalopathy and / or may delay the progression of chronic traumatic encephalopathy. Any appropriate mammal identified as having, or as being likely to have, Huntington’s disease as described herein can be treated by, for example, administering one or more therapeutic agents. For example, Tetrabenazine (Xenazine), deutetrabenazine (Austedo), valbenazine (Ingrezza), Haloperidol (Haldol), or any combination thereof can be administered to a mammal identified as having, or as being likely to have, Huntington’s disease as described herein. Having the ability to identify mammals who have, or are likely to have, Huntington’s disease as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of Huntington’s disease and / or may delay the progression of Huntington’s disease. Any appropriate mammal identified as having, or as being likely to have, prion disease as described herein can be treated by, for example, administering one or more therapeutic agents. For example, Quinacrine, Pentosan polysulfate (PPS), PRN100, or any combination thereof can be administered to a mammal identified as having, or as being likely to have, prion disease as described herein. Having the ability to identify mammals who have, or are likely to have, prion disease as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of prion disease and / or may delay the progression of prion disease. Any appropriate mammal identified as having, or as being likely to have, viral encephalitis as described herein can be treated by, for example, administering one or more therapeutic agents. For example, cyclovir (Zovirax, Sitavig), Ganciclovir, Foscarnet (Foscavir), or any combination thereof can be administered to a mammal identified as having, or as being likely to have, viral encephalitis as described herein. Having the ability to identify mammals who have, or are likely to have, viral encephalitis as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of viral encephalitis and / or may delay the progression of viral encephalitis. Any appropriate mammal identified as having, or as being likely to have, cerebrovascular disease as described herein can be treated by, for example, administering Attorney Docket No.07039-2255WO1 2022-307 one or more therapeutic agents. For example, Apixaban (Eliquis), Dabigatran (Pradaxa), Edoxaban (Savaysa), Heparin (various), Rivaroxaban (Xarelto), Warfarin (Coumadin), or any combination thereof can be administered to a mammal identified as having, or as being likely to have, cerebrovascular disease as described herein. Having the ability to identify mammals who have, or are likely to have, cerebrovascular disease as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of cerebrovascular disease and / or may delay the progression of cerebrovascular disease. Any appropriate mammal identified as having, or as being likely to have, a brain tumor as described herein can be treated by, for example, administering one or more therapeutic agents. For example, Afinitor Disperz (Everolimus), Avastin (Bevacizumab), Belzutifan, and BiCNU (Carmustine), or any combination thereof can be administered to a mammal identified as having, or as being likely to have, a brain tumor as described herein. Having the ability to identify mammals who have, or are likely to have, a brain tumor as described herein can allow clinicians and patients to proceed with treatment options that may alleviate effects of the brain tumor and / or may delay the progression of the brain tumor. In some cases, mammals (e.g., humans) identified as having, or being likely to have, AD or another neurologic / neurodegenerative disorder as described herein can undergo more regular surveillance via, for example, physical / neurological examination, blood tests to measure levels of disease-associated markers (e.g., beta-amyloid protein and / or tau protein for AD), mental status and neuropsychological testing, and / or any appropriate imaging studies (e.g., computerized tomography (CT) scans, magnetic resonance imaging (MRI), or positron emission tomography (PET) techniques such as fluorodeoxyglucose (FDG) PET imaging, amyloid PET imaging, or tau PET imaging). As discussed herein, the methods described herein also can be used to detect biomarkers for other neurodegenerative disorders, in order to identify mammals as having, or being likely to have, another neurodegenerative disorder, or to select a mammal for treatment based on whether the mammal has, or is likely to have, another neurodegenerative disorder. In some cases, a method provided herein can include Attorney Docket No.07039-2255WO1 2022-307 assessing the expression of biomarkers specific for Parkinson’s disease in NDEVs. For example, EVs derived from CSF and / or plasma can be double-immunostained for ATP1A3 and for alpha-synuclein (aSyn), to determine whether ATP1A3+EVs have altered (e.g., elevated) levels of aSyn, which would indicate that the mammal from which the CSF or plasma was obtained has, or is likely to have, Parkinson’s disease. In some cases, a method provided herein can include assessing the expression of biomarkers specific for ALS or FTD in NDEVs. For example, EVs derived from CSF and / or plasma can be triple-immunostained for ATP1A3, Tau, and TDP-43, to determine whether ATP1A3+EVs have altered (e.g., elevated) levels of Tau and / or TDP-43, which would indicate that the mammal from which the CSF or plasma was obtained has, or is likely to have, ALS or FTD. This document also provides methods for detecting and, in some cases, isolating (e.g., by immunoprecipitation) EVs derived from specific types of glial cells. For example, microglia-derived EVs can be detected by immunostaining CSF- and / or plasma-derived EVs for ITGAM, LCP1, and / or P2RY12. In some cases, astrocyte- derived EVs can be detected by immunostaining CSF- and / or plasma-derived EVs for LRP1, ITGA6, and / or EAAT1. In some cases, oligodendrocyte-derived EVs can be detected by immunostaining CSF- and / or plasma-derived EVs for LAMP2, FTH1, and / or PLP1. It is to be noted that the immunostaining in any of these methods for identifying EVs derived from specific types of brain cells can be carried out in conjunction with immunostaining for disease specific markers, such as those described herein for AD, Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, and / or brain tumor. Non-limiting examples of antibodies against cell-specific biomarkers and disease- associated biomarkers that can be used in the methods described herein are provided in TABLE 5. In some cases, polypeptides can be detected and / or quantified in EVs using a commercially-available panel (e.g., the NULISASEQ™ CNS Disease Panel 120, available from Alamar Biosciences, Fremont, CA). Polypeptides that can be evaluated using the NULISASEQ™ panel include, without limitation, ACHE, alpha-synuclein, Attorney Docket No.07039-2255WO1 2022-307 amyloid-? peptide 1-40 (A?40), APOE, CCL22, CCL26, CXCL10, FABP3, GFAP, HTT, IFNG, IL1B, NEFL, oligomeric alpha-synuclein, PARK7, phosphorylated alpha- synuclein, phosphorylated tau, phosphorylated TDP-43, ptau at T181 (P-tau181), S100B, SAA1, SOD1, T217 (P-tau217), T231 (P-tau231), TNF, TREM2, VCAM1, and VGF. This document also provides methods for generating and using solid substrates (e.g., chips) to capture EVs derived from CSF and / or plasma (e.g., brain cell-derived EVs), and for detection and quantification of disease-specific markers associated with the EVs. In general, the methods include capturing EVs on discrete spots on a solid substrate, immunostaining the captured EVs, and detecting / quantifying the immunostained molecules on the captured EVs using super-resolution microscopy for cell type- and disease-specific markers. For example, an EV-containing sample can be placed on a chip “pre-printed” with discrete spots of antibodies or aptamers against EV markers, to capture the EVs on the surface of the chip. In some cases, an EV-containing sample can be placed on a chip having discrete spots of antibodies against non-specific EV markers (e.g., CD63, CD81, and / or CD9). In some cases, an EV-containing sample can be placed on a chip having discrete spots of antibodies against markers for particular types of EVs (e.g., APT1A3 for neuronal EVs, ITGAM, LCP1, and / or P2RY12 for microglia, LRP1, ITGA6, and / or EAAT1 for astrocytes, and / or LAMP2, FTH1, and / or PLP1 for oligodendrocytes). The chip having EVs captured thereon can then be incubated with one or more labeled antibodies against markers for EVs derived from specific types of cells (e.g., neurons, astrocytes, microglia, or oligodendrocytes), and / or against markers for neurologic disorders (e.g., AD, Parkinson’s disease, ALS, FTD, multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, or brain tumor). The different antibodies can be coupled to different labels, to allow for detection of different markers in the same EVs. Any appropriate label can be used. Non-limiting examples of labels that can be used include fluorescein isothiocyanate (FITC), ALEXA FLUOR®488 (AF488), ALEXA FLUOR®647 (AF647), ALEXA FLUOR®594 (AF594), and ALEXA FLUOR®555 (AF555). After a suitable incubation period, the chip can be washed and then imaged (e.g., using dSTORM and / or SP-IRIS analysis) to detect and quantify fluorescence from the various Attorney Docket No.07039-2255WO1 2022-307 labels that are associated with the discrete EV-bound spots, allowing for determination of the types of EVs that were present in the samples and also measurement of disease- related biomarkers. In some cases, these methods may be automated. For example, a glass slide or cover slip “chip” can be “bioprinted” with a dot pattern (e.g., a 4 x 4 matrix) of capture molecules for cell type-specific EV markers associated with neurons, astrocytes, microglia, or oligodendrocytes. Once EVs are bound to the capture molecules, detection antibodies can be automatically added (e.g., labeled antibodies against biomarkers specific to different major disorders, including disorders such as AD, Lewy body dementia, progressive supranuclear palsy, and corticobasal degeneration, which typically are difficult to differentially diagnose). The chip can then be washed and imaged. It is to be noted that such an automated method can allow for high throughput screening of samples, and that the described this chip and assay can be broadly applicable to other EV- based diagnostics. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. EXAMPLES Example 1 – ATP1A3 as a target for isolating neuron-specific extracellular vesicles from human brain and biofluids METHODS AND MATERIALS Brain, cerebrospinal fluid (CSF) and plasma sample acquisitions: One cohort of brain tissues from healthy controls, two cohorts of CSF, and two cohorts of plasma samples including healthy control and AD cases were used in these studies. Postmortem brain tissues (superior temporal lobe) were obtained from the Boston University School of Medicine Brain Bank. The first cohort of control CSF, which was used for immuno- gold staining, EXOVIEW™ analysis, super-resolution imaging, western blotting, and ELISA, was obtained from the Greater Los Angeles Veteran’s Affairs Hospital as a part of the NIH NeuroBioBank. The second cohort of CSF, which was used for Simoa Attorney Docket No.07039-2255WO1 2022-307 analysis (Simren et al., Alzheimers Dement 17:1145-1156, 2021), was acquired from the Banner Sun Health Research Institute (3 AD and 3 healthy controls). The first cohort of control plasma samples, which were used for immuno-gold staining, super-resolution imaging, western blotting, and ELISA, was obtained from the Boston University School of Medicine. The second cohort of plasma, which was used for ?-amyloid analysis by super-resolution microscopy and Simoa, was acquired from the University of California, San Diego (10 healthy controls, 10 MCI, and 10 AD). All AD, MCI, and control cases were neuropathologically diagnosed by Braak stages for tau and Thal stages for amyloid ?, with short postmortem intervals. Clinical testing was performed using the MMSE (Arevalo-Rodriguez et al., Cochrane Database Syst Rev 7:CD010783, 2021) to classify individuals with MCI and AD. Participants with an MMSE score between 23 to 27 were categorized as MCI, while those with an MMSE score below 23 were categorized as AD. Human subjects from these three groups were carefully matched for age (CTL vs MCI vs AD = 82.7 vs 88.5 vs 82.5 years old, ANOVA P > 0.05) and sex (5 male and 5 female for each group). The demographic information of all cases is provided in TABLES 4A-4E. Extracellular vesicle isolation from induced hiPSC-neurons (iNeurons): Rapid induction of iPSC into human excitatory neurons was performed via a doxycycline- inducible neurogenin-2 (NGN2) system as described elsewhere (Chen et al., Nucleic Acids Res 37:W305-311, 2009). Briefly, to initiate NGN2 induction, doxycycline was added to NGN2 iPSCs at a final concentration of 2 µg / mL in fresh media consisting of KNOCKOUT™ DMEM (Invitrogen, Waltham, MA; Cat# 10829018), KNOCKOUT™ Serum Replacement (Invitrogen, Cat# 10828010), MEM-NEAA (Invitrogen, Cat# 11- 140-050), GLUTAMAX™ (Invitrogen, Cat# 35050061), and ?-mercaptoethanol (Invitrogen, Cat# 21985023). On day 2, puromycin was added at 5 µg / mL for selection. On day 4, cells were replated on poly-ornithine (10 µg / mL) (Sigma-Aldrich, Burlington, MA; Cat# P4957,) and mouse laminin (5 µg / mL; Invitrogen, Cat# 23017015) co-coated 6-well plate (1 × 106cells / well) in media consisting of Neurobasal (Gibco, Cat# 21103049), B27 (Cat# 17504044, Gibco, Waltham, MA), GLUTAMAX™, 20% dextrose (Sigma-Aldrich, Cat# G8769), MEM-NEAA supplemented with 10 ng / mL BDNF Attorney Docket No.07039-2255WO1 2022-307 (PeproTech, Cranbury, NJ; Cat# 450-02), GDNF (PeproTech, Cat# 450-10) and CNTF (PeproTech, Cat# 450-13). Conditioned media from days 17-21 were collected and processed for iNeuron-EV isolation by ultracentrifugation at 110,000 × g overnight at 4°C in a 41Ti rotor (Optima-XE SW41; Beckman Coulter, Indianapolis, IN). EVs were resuspended in PBS for further characterization. Extracellular vesicle isolation from human brain, CSF, and plasma: Unfixed frozen tissue (0.5g) from the temporal cortex of deceased control cases was processed for EV extraction based on method described elsewhere (You et al., J Extracell Vesicles, 11:e12183.2022; and Muraoka et al., Alzheimers Dement 16:896-907, 2020), with some modifications. Briefly, the tissue was sliced with a razor blade into 2-3 mm3sections on ice. The cut sections were dissociated in Hibernate-E medium (ThermoFisher Scientific, Waltham, MA; Cat# A1247601) containing 75 U / mL of collagenase type 3 (Worthington Biochemical, Lakewood, NJ; Cat# LS004180) at 37°C for 15 minutes. After incubation, protease inhibitor (ThermoFisher Scientific, Cat# PI78443) and 6 ml of ice-cold Hibernate-E were immediately added to the tissue samples without further homogenesis, and samples were then filtered with 40-µm mesh filters (ThermoFisher Scientific, Cat# 22-363-547). After filtration, the samples were sequentially centrifuged at 300 × g for 10 minutes at 4°C to precipitate large debris, 2,000 × g for 10 min at 4°C to precipitate the cellular fraction, and 5,000 × g for 20 minutes at 4°C to precipitate the plasma membrane fraction. Supernatants were filtered using a 0.45-?m polyethersulfone membrane filter (Millipore, Burlington, MA; Cat# SLHPM33RS) and ultracentrifuged at 110,000 × g for 70 minutes at 4°C using a SW41Ti rotor. The pellets were resuspended in 2 mL of 0.475 M sucrose solution (ThermoFisher Scientific, Cat# S5-3). A sucrose step gradient was generated with steps starting from 2.0M to 1.5M, 1.0M, 0.825M, 0.65M, and 0.475M to facilitate capture of the EV-rich pellet by centrifuging at 200,000 × g for 20 hours at 4°C. The final pellets from the “V” fraction (the fraction between 0.65M and 0.825M) and the “VI” fraction (the fraction between 0.825M and 1.0M) were combined as the “brain- derived EV pellet.” For CSF-derived EV extraction, the commercial EXOQUICK®EV isolation kit (System Biosciences, LLC, Palo Alto, CA; Cat# EXOQ5A-1) was used according to the Attorney Docket No.07039-2255WO1 2022-307 manufacturer’s instructions. For all the experiments, pooled CSF were used. Briefly, a 1 mL CSF sample was thawed on ice, treated with protease inhibitor, and centrifuged at 3,000 × g for 20 minutes at 4°C. The supernatant was transferred to a new tube and centrifuged at 5,000 × g for 20 minutes at 4°C. The supernatant was then added to an appropriate volume of EXOQUICK®precipitation solution and incubated overnight at 4°C. The mixture was centrifuged at 1,500 × g for 30 minutes at 4°C to precipitate the EV pellet. For plasma sampling, 500 ?L was thawed on ice, treated with protease inhibitor, and centrifuged at 1,500 × g for 10 minutes at 4°C, and the supernatant was then centrifuged at 10,000 × g for 20 minutes at 4°C. Subsequently, the EXOQUICK®ULTRA EV isolation kit (System Biosciences, LLC, Cat# E Q ULTRA-20A-1) was used to isolate plasma-EVs designated for immunoblotting according to the manufacturer’s instructions. Otherwise, qEV original columns (IZON Science; Medford, MA) were used to separate enriched EV fractions from plasma as described elsewhere (Muraoka et al., Aging Dis 12:1363-1375, 2021). Immunofluorescent (IF) staining: For human brain sections, sequential deparaffinization and antigen retrieval was performed in 1 × Co-Detection Target Retrieval Reagent (Advanced Cell Diagnostics; Newark, CA) for 15 minutes at 98°. For mouse brain sections, antigen retrieval was performed in sodium citrate for 20 minutes at 95°C, followed by rinsing 2 times with PBS. Cultured cells were washed three times with 1 × Dulbecco’s phosphate-buffered saline (DPBS) and fixed in 4% paraformaldehyde at 37°C for 15 minutes, prior to embedding into blocking buffer (1 × PBS, 5% bovine serum albumin (BSA) (Sigma-Aldrich, Cat# A7906), 5% goat (ThermoFisher Scientific, Cat# 16210-064) or donkey serum (Sigma-Aldrich, Cat# D9663), and 1% Triton X-100 (Sigma-Aldrich, Cat# T9284)) at room temperature for 1?hour. The samples were then labelled overnight at 4°C. The primary antibodies used were anti-ATP1A3 (1:1000; ThermoFisher Scientific, Cat# MA3915), anti-NCAM1 (1:1000; ThermoFisher Scientific, Cat# MA5-11563), anti-L1CAM (1:1000; ThermoFisher Scientific, Cat# 14- 1719-82), anti-MAP2 (1: 200; ThermoFisher Scientific, Cat# 13-1500), anti-glial fibrillar acidic protein (GFAP) (1:2500; Agilent Technologies, Alpharetta, GA, Cat# Z033429, Agilent), and anti-IBA1 (1:100; Wako Chemicals, Richmond, VA, Cat# 019-19741). Attorney Docket No.07039-2255WO1 2022-307 ALEXA FLUOR®secondary antibodies (Life Technologies; Waltham, MA) were conjugated to the target species at room temperature (25°C) for 1 hour. DAPI (4?,6- diamidino-2-phenylindole, 1:2500; ThermoFisher Scientific, Cat# D1306) was used to label nuclei. Images were acquired using a Leica SP8 confocal microscope (Leica; Deerfield, IL). Immunogold labeling of EVs on transmission electron microscopy: The immunogold labeling of EVs (purified iNeuron-EVs, brain-EVs, CSF-EVs, and plasma- EVs) was performed and analyzed at the Electron Microscopy Facility, Harvard Medical School, as described elsewhere (Ruan et al., Brain 144:288-309, 2021). For single immunogold labeling of CD9 on isolated EVs, 5 ?L samples containing 1 × 1010particles / mL were adsorbed for 5 minutes to carbon-coated grids (Electron Microscopy Sciences, Hatfield, PA; Cat# CF400-CU,) that had been made hydrophilic by a 20 second exposure to a glow discharge (25 mA). After adsorption, the grids were blocked with 1% BSA (Sigma-Aldrich, Cat# A7906) for 10 minutes, incubated with 5 µL drops of primary mouse anti-human CD9 antibody (1:20) (BD Biosciences, San Jose, CA; Cat# 555370) for 30 minutes, washed with four drops of PBS for 10 minutes, and then incubated in rabbit anti-mouse bridging antibody (1:50; Abcam, Cambridge, United Kingdom; Cat# ab6709) for 30 minutes, followed by PBS washes and incubation in 5-nm protein A-gold (University Medical Center, Utrecht, The Netherlands) for 20 minutes. Grids were washed with two drops of PBS followed by four drops of water (for a total 15 minutes), and subsequently stained in 1% uranyl acetate. After removing the excess uranyl acetate with a filter paper, the grids were examined using a JEOL 1200EX transmission electron microscope and images were recorded with an AMT 2k CCD camera. For double immunogold labeling of EVs, the grids were fixed for 1 minute in 1% glutaraldehyde, quenched with 4 drops of 20 mM glycine in PBS for a total of 10 minutes, followed by incubation with a first primary antibody (anti-ATP1A3, Cat# MA3915; anti-NCAM1, Cat# MA5-11563; or anti-L1CAM, Cat# 14-1719-82; all from ThermoFisher Scientific), 5-nm colloidal gold conjugated protein-A incubation, and then PBS washes. The labeling procedure was repeated with a second primary antibody (anti- Attorney Docket No.07039-2255WO1 2022-307 CD9, 1:30), followed by rabbit anti-mouse and a larger size protein A gold (10 nm). The grids were stained in uranyl acetate and imaged as described above. Super-resolution microscopy: Super-resolution images of EVs were acquired using dSTORM from ONI (Nanoimager S; Oxford Nanoimaging, Oxford, United Kingdom) equipped with a 100×, 1.4NA oil immersion objective. EV samples were immobilized on microfluidic glass slides (EV profiler Kit, EV-MAN-1.0; Oxford Nanoimaging) and stained with a pan-tetraspanin antibody cocktail consisting of FITC anti-human CD9 (HI9a; BioLegend, Cat# 312104), FITC anti-human CD81 (5A6; BioLegend, Cat# 349504), and FITC anti-human CD63 (H5C6; BioLegend, Cat# 353006), anti-ATP1A3 antibody (ThermoFisher Scientific, Cat# MA3915) conjugated to ALEXA FLUOR®555 fluorophore by commercial conjugation kit (ab269820, Abcam), AF647-conjugated anti-NCAM1 antibody (BD Biosciences, Cat# 563443) or AF647- conjugated anti-L1CAM antibody (BD Biosciences, Cat# 564194) according to the manufacturer’s instructions as described elsewhere (Gebara et al., J Extracell Vesicles 11:e12217, 2022).2500 total images were recorded for localization mapping using 30%, 30%, and 30% power on the 488 nm, 561 nm, and 640 nm lasers, respectively. Co- localization analysis of the different molecules in a single EV was conducted using the CODI online analysis platform (alto.codi.bio). Localization clusters with more than 15 individual molecules were regarded as EVs. EV clusters with Skew ranging from 1 to 2.9 and Circ ranging from 0.43 to 1 were selected for further analysis. A marker was considered to be positive in a single particle when more than 3 individual molecules were detected in the same channel within a radius of 100 nm around the center of a cluster. Five fields of view were acquired from each sample for quantitative analysis. Further, to visualize and analyze neurodegenerative disease-associated proteins by dSTORM, plasma-derived EVs were stained with FITC anti-tetraspanins (CD9, CD63, CD81), AF555-conjugated anti-ATP1A3, and AF647-conjugated anti-?-Amyloid (BioLegend, Cat #800718), AF647-conjugated anti-NCAM1, or AF647-conjugated anti-L1CAM and AF594-conjugated anti-?-Amyloid antibodies (BioLegend, Cat #800716).3000 total images were recorded for localization mapping using 30%, 30%, and 30% power on the 488 nm, 561 nm, and 640 nm lasers, respectively. A? was considered as positive in a Attorney Docket No.07039-2255WO1 2022-307 single particle when more than 2 individual molecules were detected in the same channel within a radius of 200 nm around the center of a cluster. Six fields of view were acquired from each sample for quantitative analysis by CODI platform. Single particle-interferometric reflectance imaging sensor (SP-IRIS) analysis: SP-IRIS analysis of iNeuron-EVs, brain-EVs, and CSF-EVs was performed on EXOVIEW™ Tetraspanin chips (EV-TC-TTS-01; NanoView Biosciences, Boston, MA) using the EXOVIEW™ R100 platform (NanoView Biosciences) as described elsewhere (Peng et al., J Extracellular Biol 1:e36, 2022; and Gebara et al., supra). The desired volume of EVs was diluted in buffer A to a final volume of 40 ?L. Thirty-five ?L of each diluted sample was incubated on an EXOVIEW™ Tetraspanin Chip for 16 hours at room temperature. The chips contained spots printed with anti-EV markers including CD63, CD81, and CD9 for EV capturing, or mouse IgG antibody as a control for non-specific EV binding. The chips were washed three times in 1 mL solution A, followed by incubation for 1 hour at room temperature with labeling antibodies. In these studies, an EV antibody cocktail (EV-TC-AB-01, NanoView Biosciences) containing AF488- conjugated anti-CD63, anti-CD81, and anti-CD9 antibodies, AF647-conjugated anti- ATP1A3 antibody (Novus Biologicals, Centennial, CO; Cat# NBP2-99238AF647,), AF647-conjugated anti-NCAM1 antibody (BD Biosciences, Cat# 563443), and AF647- conjugated anti-L1CAM antibody (BD Biosciences, Cat# 564194) was used for detection of EV subpopulations. In addition, an ALEXA FLUOR®555 Conjugation Kit (ab269820, Abcam) was used to conjugate AF555 fluorophores to anti-ATP1A3 antibody (ThermoFisher Scientific, Cat# MA3915) according to the manufacturer’s protocol. All antibodies were pre-diluted 1:500 in solution A. After 1 hour of incubation at room temperature, the chips were washed, dried, and then imaged with the EXOVIEW™ R100 reader using the EXOVIEW™ Scanner 3.0 acquisition software. The data were then analyzed using EXOVIEW™ Analyzer 3.0. The signal recorded on mIgG-printed spots was used as a background control for normalization. The percentage of ATP1A3+EVs, NCAM1+EVs, and L1CAM+EVs in each anti-tetraspanin spot was calculated as the ratio of AF555-positive events or AF647-positive events to the total fluorescent events × 100. Heatmaps showing total fluorescent particle counts were generated using Graphpad Attorney Docket No.07039-2255WO1 2022-307 prism 9. Two biological replicates for iNeuron-EVs, brain-EVs, and CSF-EVs were used for the assessment. Western blotting: Brain tissue, CSF, plasma, and corresponding EV fractions were lysed in cold RIPA buffer (25 mM Tris-HCl pH 7.6, 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS (ThermoFisher Scientific, Cat# 89900)) supplemented with a protease and phosphatase inhibitor mixture (ThermoFisher Scientific, Cat#78445) and sonicated for 5 minutes. Protein concentrations were measured by microBCA assay (ThermoFisher Scientific, Cat#23235). Equivalent amounts of brain lysates, CSF, plasma, and EVs were denatured in Laemlli sample buffer (Bio-Rad Laboratories, Hercules, CA; Cat# 1610737) and loaded on 4%-20% TGX stain-free SDS-PAGE gels (Bio-Rad, Cat# 4568096) or normal SDS-PAGE gels (Bio-Rad, Cat# 4561096) and then electro- transferred to 0.45 ?m nitrocellulose membranes (Bio-Rad, Cat# 1620115). The membranes were blocked with 5% non-fat milk (Cell Signaling Technology, Danvers, MA; Cat# 9999S) and incubated with primary antibodies overnight at 4°C. The following primary antibodies were utilized for immunoblots: anti-NCAM1 (1:500, ThermoFisher Scientific, Cat# MA5-11563), anti-ATP1A3 (1:500, ThermoFisher Scientific, Cat# MA3915), anti-L1CAM (1:200, ThermoFisher Scientific, Cat# 14-1719-82), anti-CD81 (1:500, BioLegend, Cat# 349502), anti-CD9 (1:500, Millipore, Cat# CBL162), anti- Cytochrome C (CytoC, 1:200, Cell Signaling Technology, Cat# 11940S), anti-GM130 (1:100, Santa Cruz Biotechnology, Cat# sc55591), anti-H2A (H2A.Z, 1:200, Cell Signaling Technology, Cat# 2718S), anti-Tau (Tau13, 1:1000, distributed by the Kanaan lab), anti-GAPDH (1:500, ThermoFisher Scientific, Cat# MA5-15738), anti- synaptophysin (SYP, 1:500, Sigma-Aldrich, Cat# S5768), anti-SNP25 (1:500, BioLegend, Cat# 836304), anti-TMEM119 (1:500, Sigma-Aldrich, Cat# HPA051870), anti-GFAP (1:500, DAKO, Cat# z0334), anti-FLOT1(1:1000, BD Biosciences, Cat# 610820), anti-Annexin A2 (1:500, Abcam, Cat# ab178677), anti-APOA1 (1:100, Santa Cruz Biotechnology, Cat# sc-376818), and anti-?-actin (1:500, Santa Cruz Biotechnology, Cat# sc-47778). The membranes were further incubated with appropriate horseradish peroxidase (HRP)-labelled secondary antibodies (anti-mouse IgG, HRP- linked antibody, Cell Signaling Technology, Cat# 7076S; anti-rabbit IgG, HRP-linked Attorney Docket No.07039-2255WO1 2022-307 antibody, Cell Signaling Technology, Cat# 7074S) for 1 hour, and immunoreactivity was captured using enhanced chemiluminescence solutions (Millipore, Cat# WBKLS0100). For silver staining, the protein gels were fixed and stained according to the manufacturer’s instructions (ThermoFisher Scientific, Cat# 24612). All images were detected using the ChemiDoc MP Imaging System (Bio-Rad). For quantification analysis, band densities were digitally measured by ImageJ software (NIH). For proteinase protection assays conducted as illustrated in FIG.9A, equivalent amounts of brain-derived EVs (5 µg) were incubated with 20 ?g / mL proteinase K (PK, QIAGEN, Hilden, Germany; Cat# 19131) and 5 mM CaCl2 in PBS for 1 hour at 37°C with gentle vortexing every 15 minutes. The EVs with or without PK treatment were loaded for immunoblotting as described above. Immunocapture of ATP1A3+, NCAM1+and L1CAM+EVs from brain, CSF, and plasma: Immunocapture of specific EVs from bulk EVs were performed as described elsewhere, with minor modifications (You et al., J Extracell Vesicles 11:e12183, 2022). Antibodies against potential NDEV markers ATP1A3 (ThermoFisher Scientific, MA3915), NCAM1 (ThermoFisher Scientific, MA5-11563), and L1CAM (ThermoFisher Scientific, 14-1719-82) were conjugated to Dynabeads M-270 Epoxy using the Dynabeads Antibody Coupling Kit (ThermoFisher Scientific, Cat# 14311D) according to the manufacturer’s instructions. Equal amounts of total brain-EVs (40 ?g) isolated from three individual healthy controls or pooled CSF-EVs (25 ?g) isolated from healthy controls or AD cases were initiated for immunoprecipitation. The EV samples were pretreated with 20 ?L human FcR receptor blocking solution (Miltenyi Biotec, North Rhine-Westphalia, Germany; Cat# 130-059-901) on ice for 15 minutes and then incubated with antibody-conjugated bead complex (5 ?g / mg) in a final volume of 500 ?L. As a negative control, immunoglobulin G (IgG)-conjugated beads were added to the mixed EVs from brain or CSF samples. After overnight incubation at 4°C, immunoprecipitated NDEVs were eluted in an equal volume of cold RIPA buffer containing protease inhibitor and divided for downstream mass spectrometry, western blotting, and ELISA. The immunoprecipitated EVs were filtered in a 0.45 ?m Spin-X centrifuge tube (Corning, Corning, NY; Cat# CLS8162) to completely remove magnetic Attorney Docket No.07039-2255WO1 2022-307 beads. The total EVs and immunocaptured EVs were used for immunoblotting as described above. For EV particle analysis, IgG elution buffer (ThermoFisher Scientific, Cat# 21028T) was used for elution, followed by pH neutralization with 1M Tris-buffer. Mass spectrometry and data analysis: Total brain-EVs (5 ?g; n = 3) and immunoprecipitated EVs (n = 3 for NDEVs; n = 2 for mIgG control) were subjected to label-free quantitative mass spectrometry as described elsewhere (You et al., J Extracell Vesicles 9:1706801, 2020). First, EV samples were resuspended in 1× Laemmli sample buffer (Bio-Rad, Cat# 1610747) with 2-mercaptoethanol and heated at 95°C for 5 minutes. The samples were loaded onto an 10% SDS-PAGE gel (Bio-Rad, Cat# 4561033) and run until 1 cm off the loading well. The entire protein region of the gel was excised after Coomassie staining and subjected to in-gel trypsin digestion after reduction with dithiothreitol and alkylation with iodoacetamide. Peptides eluted from the gel were lyophilized and reconstituted in 25-50 µL of 5% acetonitrile containing 0.1% (v / v) Formic acid (Suprapur, Cat# 1116700250, EMD Millipore Corporation) with 1 pmol ADH digest and analyzed on a NanoACQUITY UPLC®(Waters Corporation, Milford, MA) coupled to a Orbitrap Fusion Lumos Tribrid mass spectrometer (ThermoFisher Scientific). A 1-2 µL injection was loaded at 4 µL / min for 4 minutes onto a custom- packed fused silica pre-column (kasil frit, 100 µm I.D.) with 2 cm of ProntoSIL C18AQ (Bischoff Chromatography, Atlanta, GA; 200Å, 5µm). Peptides were then separated on a 75 µm I.D. fused silica analytical column packed with 25 cm Magic C18AQ (Bruker- Michrom, Fremont, CA; 100Å, 3µm) particles to a gravity-pulled tip. Peptides were eluted at 300 nL / min using a linear gradient from 5-35% of mobile phase B (0.1% (v / v) formic acid in acetonitrile) in mobile phase A (0.1% (v / v) formic acid in water) in 115 minutes. Ions were introduced by positive electrospray ionization via liquid junction at 1.4-1.6 kV into a Orbitrap Fusion Lumos Tribrid mass spectrometer. Mass spectra were acquired from m / z 300-1750 at a resolution of 120,000 (m / z 200), maximum injection time of 50 ms using an AGC target of 4 × 105, and data-dependent acquisition (3 sec cycle time) for tandem mass spectrometry by HCD fragmentation using an isolation width of 1.6 Da, max fill time of 22 ms, with an AGC target of 5 × 104. Peptides were Attorney Docket No.07039-2255WO1 2022-307 fragmented using a collision energy of 30%, and fragment spectra were acquired at a resolution of 15000 (m / z 200). Raw data files were processed with Proteome Discoverer (ThermoFisher Scientific, version 2.1) and searched with Mascot Server (Matrix Science, version 2.6) against the Human (Swissprot) FASTA file (downloaded 04 / 09 / 2019). Tryptic specificity (up to two missed cleavages), a 10-ppm mass tolerance for the precursor, and a 0.05 Da mass tolerance for the fragments were used as search parameters. All non-filtered search results were processed by Scaffold (Proteome Software Inc, version 5.1.0) with threshold values set at 95% for peptides and 99% for proteins (two peptide minimum) using the Trans-Proteomic Pipeline (Institute for Systems Biology). Immunoprecipitated proteins were further selected after exclusion of keratins as contaminates and non-specific proteins co-immunoprecipitated by isotype control IgG. Protein comparison was conducted using label-free intensity-based absolute quantification (iBAQ) method and further normalized by the average of ADH iBAQ across all the samples. The 0 iBAQ values were replaced with 1 for calculation purposes. Fold expression of overlapping proteins in ATP1A3+EVs versus NCAM1+EVs, and ATP1A3+EVs versus L1CAM1+EVs was calculated from the individual median averaged protein normalized iBAQ values within each group. Functional pathway analyses including Gene Ontology analysis, KEGG pathway analysis and Cell Atlas enrichment analysis of potential NDEV signatures were performed using the ToppGene Suite online tool (Chen, et al., Nucleic Acids Res 37:W305-311, 2009) with FDR corrected P-value < 0.05 (toppgene.cchmc.org). Heatmaps showing AD-related proteins and Neuronal type proteins among ATP1A3+EVs, NCAM1+EVs, and L1CAM+EVs were generated using Log2 iBAQ protein intensity. The final visualization of a venn diagram, gene ranking doplots, pathway bubble plots, and heatmaps was performed using R program (version 4.1.0). Enzyme-linked immunosorbent assay (ELISA): Commercial ELISA kits were used to evaluate the protein concentration of ATP1A3 (Aviva Systems Biology, San Diego, CA; Cat# OKEH05672), NCAM1 (Abcam, Cat# ab119587), and L1CAM1 (Abcam, Cat# ab278114) in immunocaptured EVs from CSF and plasma according to the Attorney Docket No.07039-2255WO1 2022-307 manufacturer’s instructions. Duplicate wells were assayed in each case, with four biological replicates for each group. Nanoparticle tracking analysis (NTA) of extracellular vesicles: The size distribution and concentration of EVs were analyzed by NTA using a NanoSight NS300 instrument (Malvern, Worcestershire, United Kingdom). Isolated EVs from iNeurons, brain, or CSF were pre-diluted in filtered PBS to achieve a concentration within the range of about 107-108particles / mL for optimal quantification. For each sample, 700 µL diluted EVs were injected into a sample-carrier cell, and the particles were automatically tracked and sized using Brownian motion and diffusion coefficients to record four videos of 30 second each. The parameters were set at 22.5°C ± 0.5°C for detection level 5 and camera level 13-15. The size mode (nm), mean size (nm), and concentration (particle number / mL) of the EVs were calculated by combining the data from the four records. Simoa assays: Simoa assays including Neurology 3-Plex A (TAU, A?42, and ??40), P-tau181 (V2), and SNAP-25 were conducted on the Simoa HD-X analyzer according to the manufacture’s instruction (Quanterix, Billerica, MA). Pooled CSF, corresponding total CSF-EVs, and ATP1A3+EVs (45 µL in elution buffer) from healthy controls (n = 3) or AD (n = 3) were lysed with equal amounts of M-PER Mammalian Protein Extraction Reagent (ThermoFisher Scientific, Cat# 78503) and protease inhibitor cocktail (ThermoFisher Scientific, Cat# 78442). IgG immunoprecipitation from mixed CSF-EVs was used as a negative control. CSF samples were centrifuged at 10,000 × g for 5 minutes at 4°C and plasma samples were centrifuged at 2,000 × g for 10 minutes at 4°C, prior to dilution with assay specific sample diluent provided in the assay kits. The relative concentration estimates were calculated according to the sample standard curve. Data collection was conducted using Microsoft Excel, while analysis and graphing were performed using GraphPad Prism (version 9.0). Statistical analysis: All data are presented as mean ± SEM where indicated. Statistical analyses, including the calculation of Pearson correlation coefficients for correlation analysis and area-under-the-curve (AUC) values from receiver-operating characteristic (ROC) analysis, were performed using GraphPad Prism (version 9.0). Comparisons within two groups were analyzed for significance using Student’s unpaired Attorney Docket No.07039-2255WO1 2022-307 two-tailed t-test or paired two-tailed t-test. Comparisons among three or more groups were performed with Ordinary one-way ANOVA with Tukey’s post hoc test, or Kruskal- Wallis nonparametric ANOVA with Dunn’s post hoc test if the data failed to pass normality tests of Shapiro-Wilk. Statistical significance was defined as P value < 0.05. P values in functional enrichment analyses were adjusted for multiple comparisons using FDR correction with the Benjamini-Hochberg method where indicated. Boxplots represent the median, 25th and 75th percentiles and whiskers represent measurements to the 5th and 95th percentiles. RESULTS ATP1A3 is a neuron-specific protein and associated with EVs in human brain tissues and biofluids Immunofluorescent staining of ATP1A3 protein in adult mouse brain revealed its abundant expression across different brain regions, including the cortex, hippocampus, striatum, and thalamus (FIG.1A). To investigate the cell type-specific expression of ATP1A3, colocalization analysis was conducted for ATP1A3 and specific cell markers, including markers for neurons (MAP2+), astrocytes (GFAP+), and microglia (IBA1+), in the hippocampal area of both wild-type mice (WT) and an AD mouse model (APPNL-G-F; FIG.1B). Additionally, a similar analysis was performed using human brain tissues obtained from healthy individuals and patients with AD (FIG.1C). These data showed a higher degree of overlap in fluorescence intensity and distribution between ATP1A3 and the neuronal marker MAP2, as compared to GFAP and IBA1 staining, in all experimental conditions, strongly suggesting that ATP1A3 expression is predominantly specific to neurons. RNA expression data accessed from the Human Protein Atlas database further supported this observation, demonstrating a more confined expression pattern of ATP1A3 in the brain with a notable enrichment in neurons, as compared to the expression pattern of NCAM1 and L1CAM (FIG.2). ATP1A3 is a multiple transmembrane protein expressed on neurons, indicating that it might be associated with EVs on their surface. EVs were therefore derived from human induced pluripotent stem cell-derived excitatory neurons (iNeurons), human brain Attorney Docket No.07039-2255WO1 2022-307 tissues, cerebrospinal fluid (CSF), and plasma, and the presence of molecules of interest was characterized using four complementary techniques (FIG.3A). iNeuron differentiation was induced by overexpressing the neuronal transcriptional factor neurogenin-2 after puromycin selection of transduced cells (Zhang et al., Neuron 78:785- 798, 2013), resulting in over 97% MAP2+neuronal cells with less contamination of GFAP+astrocytes (FIGS.4A and 4B). The high purity of the culture was also supported by a proteomics dataset described elsewhere (You et al., J Extracell Vesicles 11:e12183, 2022), showing a remarkable enrichment of neuron-specific proteins including MAP2, MAPT, and synaptic proteins in iNeurons (FIG.4C). In addition, NDEV marker candidates including ATP1A3, NCAM1, and L1CAM were also detected (FIG.4D). Immuno-electron microscopy also was used to confirm the presence of ATP1A3, NCAM1, and L1CAM on the EV surface, by labeling EVs with 5-nm gold particles for these markers and 10-nm gold particles for CD9. Immuno-labeling of CD9 was detectable in iNeuron-, brain-, CSF-, and plasma-EVs (FIG.3B, left column). Double- immunostaining showed that ATP1A3, NCAM1, and L1CAM were detected with CD9 in a single EV in all of these samples (FIG.3B, 2nd-4thcolumns). A SP-IRIS (Peng et al., J Extracellular Biol 1:e36, 2022) analysis was employed to determine the population of these NDEV markers in different EV preparations after EV affinity binding to tetraspanins on EXOVIEW™ chips (FIG.5A). Total fluorescent particles in each spot pre-conjugated with anti-CD9, anti-CD81, anti-CD63, and isotype control IgG antibodies were counted in EV samples, revealing the different tetraspanin subpopulations between iNeuron-, brain-, and CSF-EVs (FIGS.5B and 5C). Fluorescence analysis of the NDEV markers confirmed the presence of ATP1A3, NCAM1, and L1CAM in those EV preparations, and revealed their co-localization with pan-tetraspanins. The captured iNeuron-EVs displayed a higher level of ATP1A3 compared to NCAM1 and L1CAM, particularly in CD9 captured spots (FIGS.3C and 3D). Intriguingly, a higher percentage of NCAM1+particles was observed in CD9 and CD81 captured spots from brain-EV, while ATP1A3+particles were more enriched in CD63 captured spots from brain- and CSF-EV (FIGS.3E and 3F). The co-localization analysis showed diverse EV subpopulations (e.g., pan-tetraspanins+EVs, ATP1A3+EVs, Attorney Docket No.07039-2255WO1 2022-307 NCAM1+EVs, L1CAM+EVs, ATP1A3+NCAM1+EVs, ATP1A3+L1CAM+EVs, etc.) in brain- and CSF-EVs (FIG.5D), suggesting the heterogeneity of neuronal EVs in human samples. Single- and bulk-EV analysis demonstrated greater enrichment of ATP1A3- associated EVs than NCAM1 and L1CAM in human samples To confirm the expression and colocalization of surface markers in four EV preparations, super-resolution imaging of single EVs captured by EV profiler kit (ONI) and stained with fluorescent antibodies against pan-tetraspanins (CD9 / CD81 / CD63) and neuronal EV markers (ATP1A3, NCAM1, L1CAM) was performed at a single vesicle resolution by dSTORM (Gebara et al., J Extracell Vesicles 11:e12217, 2022) (FIG.6A). The clustering analysis showed a higher percentage of ATP1A3+EV subpopulation when compared to NCAM1 in iNeuron-EVs (35.7 vs 0.0%), CSF-EVs (56.8 vs 0.5%) and plasma-EVs (11.4 vs 0.9%), while fewer ATP1A3+EVs were identified compared to NCAM1 in brain-EVs (12.5 vs 33.1%, FIGS.6B and 6C). Similarly, a greater ATP1A3+EV subpopulation was detected as compared to L1CAM in iNeuron-EVs (20.4 vs.0.1%), brain-EVs (19.4 vs 4.5%), CSF-EVs (29.7 vs 0.9%), and plasma-EVs (8.1 vs 0.2%, FIGS.6D-6F). Thus, these data demonstrated that the three candidate markers were present on the surface of EVs isolated from iNeurons, brain, CSF, and plasma, and that the ATP1A3+EVs were more reliably detectable in these human biospecimens than NCAM1+and L1CAM+EVs by dSTORM techniques. Next, EVs from brain, CSF, and plasma samples were biochemically characterized. Immunoblotting confirmed the expression of EV specific markers (CD9 and CD81) and the absence of non-EV markers (GM130, CytoC, and H2A) in brain-EVs (FIG.7A). Notably, immunoblotting showed that ATP1A3 exhibited significantly higher enrichment in EV fractions compared to brain lysates, while no such enrichment was observed for NCAM1 and L1CAM (FIG.7B). In CSF and plasma samples, ATP1A3 was also highly enriched in EV fractions, while both NCAM1 and L1CAM were rather depleted in EVs (FIGS.8A and 8B). To determine if the three NDEV markers were expressed on the EV surface, a proteinase treatment assay (FIG.9A) was performed. Proteinase K treatment significantly diminished the amount of ATP1A3, NCAM1, Attorney Docket No.07039-2255WO1 2022-307 L1CAM, and CD81 in brain-EVs compared to microtubule-associated protein tau (Tau) and GAPDH, which are EV intraluminal proteins (Ruan et al., Brain 144:288-309, 2021; and Dar et al., Nat Commun 12:6666, 2021) (FIGS.9B and 9C). These biochemical studies confirmed that ATP1A3 is associated with the neuronal EV surface, and is enriched in human brain-, CSF-, and plasma- EV samples compared to NCAM1 and L1CAM. ATP1A3+EVs immunoprecipitated from human brain tissues display higher neuronal cell-type specificity than NCAM1+and L1CAM+EVs by label-free mass spectrometry EV cargo molecules can reflect the physiological or disease status of the cells of origin (Kalluri and LeBleu, Science 367(6478):eaau6977, 2020). To characterize the signature of cargo molecules in three different NDEVs, proteomic analysis of ATP1A3-, L1CAM-, and NCAM1-associated brain-EVs that had been separated by affinity capture was performed (FIG.10A). First, markers for EV, synapse, and glia were examined in ATP1A3+, NCAM1+, and L1CAM+EV immunocaptured from equal amounts of brain- EVs by immunoblotting (FIG.10B). Common EV markers (e.g., FLOT1, CD81, and CD9) were present in all the immunoprecipitated EV samples (FIG.10B). A greater enrichment of neuron-specific proteins, including Tau, synaptophysin (SYP), and synaptosome-associated protein 25 (SNAP25) was observed with ATP1A3 and NCAM1 immunoprecipitation than with L1CAM immunoprecipitation (FIG.10B). In addition, presumed glia markers (microglial TMEM119 and astrocytic GFAP) were undetectable in these immunoprecipitated NDEVs. Label-free liquid chromatography-mass spectrometry analysis of ATP1A3+, NCAM1+, and L1CAM+brain-EVs identified a total of 318 proteins in ATP1A3+EVs, 275 proteins in NCAM1+EVs, and 131 proteins in L1CAM+EVs (TABLES 1A-1B) after the exclusion of non-specific proteins that were co-immunoprecipitated by isotype control IgG (FIGS.10C and 10D). The resulting heatmap displayed the clustering of a total of 507 identified EV proteins, which included neuronal markers (ATP1A3, NCAM1, and L1CAM), common EV markers (e.g., CD9 and CD81), and neuron-specific molecules (e.g., SYP, SNAP25, and neuroplastin (NPTN)) (FIG.11A). Among the 249 overlapping proteins between ATP1A3+and Attorney Docket No.07039-2255WO1 2022-307 NCAM1+EVs, differentially expressed proteins (DEPs) were ranked based on their fold change in abundance. The ranking revealed a greater enrichment of neuron-specific proteins, including microtubule-associated protein 1B (MAP1B), syntaxin-1B (STX1B), SNAP25, synaptotagmin-1 (SYT1), and calcium / calmodulin dependent protein kinase II alpha (CAMK2A) in ATP1A3+EVs versus NCAM1+EVs (FIG.10E). Similarly, compared to L1CAM1+EVs, the top DEPs in ATP1A3+EVs also included neuronal proteins such as SYT1, CAMK2A, contactin-associated protein 1 (CNTNAP1), and SNAP25 (FIG.10E), demonstrating the superior enrichment of neuronal molecules in ATP1A3+EVs over NCAM1+or L1CAM1+EVs. Gene set enrichment analysis of affinity purified EVs demonstrated that proteins in ATP1A3+, NCAM1+, and L1CAM+EVs were significantly associated with not only synaptic molecules but also with myelin sheath, neurodegenerative diseases, and oxidative phosphorylation (FIGS.10F and 11B). Gene set enrichment analysis of 68 unique proteins in ATP1A3+EVs also was related to similar pathways, whereas 24 unique proteins in NCAM1+EVs were enriched in fatty acid biosynthesis, vesicle endocytosis, and secretion (FIG.11C). Proteins associated with AD and neuronal markers among the three groups also were examined by heatmaps, which showed a unique enrichment of the AD-related molecules disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), reticulon-3 (RTN3), and mitogen-activated protein kinase 1 (MAPK1) in ATP1A3+EVs, as well as enrichment of the neuronal proteins reticulon-1 (RTN1), sodium channel protein type 2 subunit alpha (SCN2A), and calcium / calmodulin-dependent protein kinase type II subunit beta (CAMK2B) (FIG.10G). These results demonstrated that cargo molecules in ATP1A3+EVs comprehensively reflect neuronal and disease changes in the brain. Increased A? levels in ATP1A3+EVs derived from CSF and plasma of AD cases Further work was conducted to isolate potential NDEVs from human biofluids by immunocapturing ATP1A3 and other molecules to investigate the application of such NDEVs to biomarker discovery for neurological diseases, such as AD (FIG.12A). Total EVs were extracted from CSF and plasma, and NDEVs were immunocaptured by specific antibodies. The immunocaptured target molecules were evaluated by western blotting and ELISA kits, showing greater enrichment of ATP1A3 in EV fractions as Attorney Docket No.07039-2255WO1 2022-307 compared to immunocapture with NCAM1, L1CAM, or control isotype IgG antibody in CSF-EVs (FIGS.13A and 13B). Similar enrichment of ATP1A3 as compared to NCAM1 and L1CAM was observed in plasma EVs using specific antibodies (FIGS.14A and 14B). Additionally, the particle distribution of affinity-enriched ATP1A3+, NCAM1+and L1CAM+CSF-EVs was evaluated by nanoparticle tracking analysis (FIGS.15A and 15B). The particle numbers were reduced after immunoprecipitation of NDEVs, reflecting the selection by affinity enrichment (FIG.15B). ATP1A3+CSF-EV samples were tested for quantification of AD biomarkers, including amyloid-? peptides 1-40 (A?40) and 1-42 (A?42), total tau (T-tau), p-tau at T181 (P-tau181) (Zetterberg, Alzheimers Dement 18(9):1687-1693, 2022), and the neuronal protein SNAP25 using high-sensitivity digital ELISA (Simoa) (Rissin et al., Nat Biotechnol 28:595-599, 2010). All of the AD biomarkers were detected in ATP1A3+CSF-EVs from both control and AD samples (FIG.12B, n = 3 per group). SNAP25 was undetectable in AD samples, likely due to synaptic loss in the AD brain (Pereira et al., Brain 144:310-324, 2021) (TABLE 2 and FIG.12B). Interestingly, the A?42 / 40 ratio in ATP1A3+CSF-EVs was elevated in AD group compared to CSF or total CSF-EVs (FIG. 12C), suggesting the higher sensitivity for the detection of changes in A?42 / 40 ratio using ATP1A3+CSF-EVs compared to CSF or total CSF-EV samples. To investigate the diagnostic potential of plasma-derived ATP1A3+NDEVs as biomarkers in neurodegenerative diseases, plasma-EVs were isolated from 10 age- and sex-matched healthy controls (CTL), 10 mild cognitive impairment (MCI) patients, and 10 AD patients, and single particle analysis of EVs fluorescently stained with pan- tetraspanins (CD9 / CD81 / CD63), ATP1A3, and A? (clone 4G8) was performed by dSTORM (FIGS.12D and 16A). The particle size distribution of plasma derived EVs were different among the three groups (FIGS.16A and 16B). In particular, an increased frequency of 50-100 nm particles was observed in the MCI group compared to the control and AD groups, likely indicating an active release of small EVs in response to early pathological changes (Chen et al., Neural Regen Res 18:587-593, 2023). The single EV- based quantitative analysis demonstrated a significantly higher percentage of A?+EVs in AD compared to healthy controls and MCI patients (FIG.16C). Intriguingly, a Attorney Docket No.07039-2255WO1 2022-307 significant increase in the A?+population was observed in ATP1A3+EVs (Pan+??+ATP1A3+ / Pan+ATP1A3+ratio) from AD patients compared to the control and MCI groups (FIGS.12E and 12F). To examine whether the elevation in A?+EV population with AD was specific to ATP1A3-associated EVs, single-EV analysis of A? levels was performed with NCAM1+and L1CAM+EVs from plasma samples of 5 controls and 5 AD patients (FIGS.17A and 17C). In line with the findings shown in FIGS.6A-6F, the number of NCAM1+and L1CAM+EVs in plasma was much lower (FIG.17B, Pan+NCAM1+??-: CTL vs AD = 0.075% vs 0.408%, Pan+NCAM1+??+: CTL vs AD = 2.63% vs 1.33%; FIG.17D, Pan+L1CAM+??-: CTL vs AD = 1.178% vs 0.042%, Pan+L1CAM+??+: CTL vs AD: 3.78% vs 0.29) than ATP1A3+EVs (FIG.17C, Pan+ATP1A3+??-: CTL vs AD = 50.85% vs 38.25%, Pan+ATP1A3+??+: CTL vs AD = 1.27% vs 14.13%). It is noted that the limited frequency of detecting NCAM1+and L1CAM+EVs in plasma has posed challenges to their utilization for biomarker development, apparently in contrast to ATP1A3+plasma-EVs as described herein. Further, it was found that the A?+population in ATP1A3+plasma EVs was positively correlated with tau pathology as defined by Braak stage, and negatively correlated with cognitive assessments including MMSE and DRS (FIG.12G). Conventional AD blood biomarkers, including A?40, A?42, A?42 / 40 ratio, and total tau (T-tau) also were quantified by Simoa using the same total plasma samples (TABLE 3). In total plasma, there was a marginal but significant decrease in the A?42 / A?40 ratio in the AD group as compared to controls, while there was no difference in other parameters (FIGS.12H and 18). Receiver-operating characteristics (ROC) curves were analyzed to compare the diagnostic accuracy of these potential plasma biomarkers. Across all comparisons, the highest AUC values were seen with % A?+population in ATP1A3+EVs; AUC values were 0.95 for AD vs controls (FIG.12I), 0.94 for AD vs MCI (FIG. 12J). AUC values for plasma A?42, A?40, A?42 / A?40, ratio and T-tau were 0.71, 0.52, 0.86, and 0.56, respectively, for AD vs controls (FIG.12I), and 0.54, 0.61, 0.60, and 0.55, respectively, for AD vs MCI (FIG.12J). Thus, these findings demonstrated the utility of ATP1A3+EVs as diagnostic blood biomarkers for neurodegenerative disorders, including AD. Attorney Docket No.07039-2255WO1 2022-307 Taken together, the studies described herein demonstrated that ATP1A3 is a promising NDEV marker in human brain, CSF, and plasma. Unlike the frequently used markers L1CAM and NCAM1, ATP1A3 expression is more restricted to neurons in the CNS and is enriched in EVs from brain and biofluids. The work described herein successfully characterized EV-specific protein cargos immunoprecipitated from human brain samples, and demonstrated that ATP1A3+EVs exhibited higher enrichment of neuronal molecules than L1CAM1+and NCAM1+EVs, indicating that ATP1A3 represents a bona fide NDEV marker. In addition, these studies demonstrated the clear presence of ATP1A3+EV in human CSF and plasma samples, revealing the high potential to access NDEVs from a liquid biopsy. Of note, the A?+population in ATP1A3+plasma-EVs displayed better discrimination of AD from healthy controls and MCI patients than conventional biomarkers, indicating that blood biomarkers for neurodegenerative diseases can be assayed by isolating circulating NDEVs. Moreover, the application of dSTORM as a single-EV analysis platform enables the characterization of loading of disease-specific biomarkers at single molecule resolution, which can improve the sensitivity and accuracy of disease detection (Ferguson et al., Sci Adv 8:eabm3453, 2022).

[0002] Attorney Docket No.07039-2255WO1 2022-307 TABLE 1A: Total identified proteins from brain-derived EVs by label-free mass spectrometry Identified Proteins Accession NumberMolecularAlternate WeightOrder ID Alcohol dehydrogenase 1 OS=Saccharomyces cerevisiae(strain ATCC 204508 / S288c) |ADH1 PE=1 SV=5sp|P00330|ADH1_YEAST 37 kDa 1 ADH1Sodium / potassium-transporting ATPase subunit alpha-2OS=Homo sapiens OX=9606 |ATP1A2 PE=1 SV=1sp|P50993|AT1A2_HUMAN 112 kDa 5 ATP1A2Sodium / potassium-transporting ATPase subunit alpha-3OS=Homo sapiens OX=9606 |ATP1A3 PE=1 SV=3sp|P13637|AT1A3_HUMAN 112 kDa 6 ATP1A3Isoform 3 of Sodium / potassium-transporting ATPase subunitalpha-1 OS=Homo sapiens OX=9606 |ATP1A1sp|P05023-3|AT1A1_HUMAN (+1) 110 kDa 8 ATP1A1Tubulin beta-4B chain OS=Homo sapiens OX=9606|TUBB4B PE=1 SV=1sp|P68371|TBB4B_HUMAN 50 kDa 9 TUBB4BTubulin beta-4A chain OS=Homo sapiens OX=9606|TUBB4A PE=1 SV=2sp|P04350|TBB4A_HUMAN 50 kDa 10 TUBB4ATubulin beta-2A chain OS=Homo sapiens OX=9606|TUBB2A PE=1 SV=1sp|Q13885|TBB2A_HUMAN 50 kDa 11 TUBB2ATubulin beta chain OS=Homo sapiens OX=9606 |TUBBPE=1 SV=2sp|P07437|TBB5_HUMAN 50 kDa 12 TUBBTubulin beta-3 chain OS=Homo sapiens OX=9606 |TUBB3PE=1 SV=2sp|Q13509|TBB3_HUMAN 50 kDa 13 TUBB3Tubulin alpha-1B chain OS=Homo sapiens OX=9606|TUBA1B PE=1 SV=1sp|P68363|TBA1B_HUMAN 50 kDa 14 TUBA1BIsoform 2 of Tubulin alpha-4A chain OS=Homo sapiensOX=9606 |TUBA4Asp|P68366-2|TBA4A_HUMAN (+1) 48 kDa 15 TUBA4AIsoform 2 of Tubulin alpha-1A chain OS=Homo sapiensOX=9606 |TUBA1Asp|Q71U36-2|TBA1A_HUMAN (+1) 46 kDa 16 TUBA1AGuanine nucleotide-binding protein G(o) subunit alphaOS=Homo sapiens OX=9606 |GNAO1 PE=1 SV=4sp|P09471|GNAO_HUMAN 40 kDa 17 GNAO1Dihydropyrimidinase-related protein 2 OS=Homo sapiensOX=9606 |DPYSL2 PE=1 SV=1sp|Q16555|DPYL2_HUMAN 62 kDa 18 DPYSL2V-type proton ATPase subunit B, brain isoform OS=Homosapiens OX=9606 |ATP6V1B2 PE=1 SV=3sp|P21281|VATB2_HUMAN 57 kDa 19 ATP6V1B2

[0003] Attorney Docket No.07039-2255WO1 2022-307 Actin, cytoplasmic 2 OS=Homo sapiens OX=9606 |ACTG1PE=1 SV=1sp|P63261|ACTG_HUMAN 42 kDa 20 ACTG1Plasma membrane calcium-transporting ATPase 4OS=Homo sapiens OX=9606 |ATP2B4 PE=1 SV=2sp|P23634|AT2B4_HUMAN 138 kDa 21 ATP2B4Isoform 2 of Sodium / potassium-transporting ATPase subunitbeta-1 OS=Homo sapiens OX=9606 |ATP1B1sp|P05026-2|AT1B1_HUMAN (+1) 35 kDa 22 ATP1B1Isoform 2 of V-type proton ATPase 116 kDa subunit aisoform 1 OS=Homo sapiens OX=9606 |ATP6V0A1sp|Q93050-1|VPP1_HUMAN (+1) 96 kDa 23 ATP6V0A1Isoform D of Plasma membrane calcium-transportingATPase 1 OS=Homo sapiens OX=9606 |ATP2B1sp|P20020-1|AT2B1_HUMAN 139 kDa 24 ATP2B1Creatine kinase B-type OS=Homo sapiens OX=9606 |CKBPE=1 SV=1sp|P12277|KCRB_HUMAN 43 kDa 25 CKBHexokinase-1 OS=Homo sapiens OX=9606 |HK1 PE=1SV=3sp|P19367|HXK1_HUMAN 102 kDa 26 HK1Isoform 2 of V-type proton ATPase catalytic subunit AOS=Homo sapiens OX=9606 |ATP6V1Asp|P38606-2|VATA_HUMAN 65 kDa 27 ATP6V1AIsoform 2 of Clathrin heavy chain 1 OS=Homo sapiensOX=9606 |CLTCsp|Q00610-2|CLH1_HUMAN (+1) 188 kDa 28 CLTCContactin-1 OS=Homo sapiens OX=9606 |CNTN1 PE=1SV=1sp|Q12860|CNTN1_HUMAN 113 kDa 29 CNTN1Syntaxin-binding protein 1 OS=Homo sapiens OX=9606|STXBP1 PE=1 SV=1sp|P61764|STXB1_HUMAN 68 kDa 30 STXBP1Isoform CNPI of 2',3'-cyclic-nucleotide 3'-phosphodiesteraseOS=Homo sapiens OX=9606 |CNPsp|P09543-2|CN37_HUMAN (+1) 45 kDa 31 CNPGuanine nucleotide-binding protein G(i) subunit alpha-2OS=Homo sapiens OX=9606 |GNAI2 PE=1 SV=3sp|P04899|GNAI2_HUMAN 40 kDa 32 GNAI2Isoform XB of Plasma membrane calcium-transportingATPase 2 OS=Homo sapiens OX=9606 |ATP2B2sp|Q01814-8|AT2B2_HUMAN 134 kDa 33 ATP2B2Annexin A6 OS=Homo sapiens OX=9606 |ANXA6 PE=1SV=3sp|P08133|ANXA6_HUMAN 76 kDa 34 ANXA6Cytoplasmic dynein 1 heavy chain 1 OS=Homo sapiensOX=9606 |DYNC1H1 PE=1 SV=5sp|Q14204|DYHC1_HUMAN 532 kDa 35 DYNC1H1

[0004] Attorney Docket No.07039-2255WO1 2022-307 Isoform 2 of Dynamin-1 OS=Homo sapiens OX=9606|DNM1sp|Q05193-2|DYN1_HUMAN (+1) 97 kDa 36 DNM1ATP synthase subunit beta, mitochondrial OS=Homo sapiensOX=9606 |ATP5F1B PE=1 SV=3sp|P06576|ATPB_HUMAN 57 kDa 37 ATP5F1BVesicle-fusing ATPase OS=Homo sapiens OX=9606 |NSFPE=1 SV=3sp|P46459|NSF_HUMAN 83 kDa 38 NSFSynaptosomal-associated protein 25 OS=Homo sapiensOX=9606 |SNAP25 PE=1 SV=1sp|P60880|SNP25_HUMAN 23 kDa 39 SNAP25Isoform 2 of Excitatory amino acid transporter 1 OS=Homosapiens OX=9606 |SLC1A3sp|P43003-2|EAA1_HUMAN (+1) 55 kDa 40 SLC1A3Isoform 2 of 4F2 cell-surface antigen heavy chain OS=Homosapiens OX=9606 |SLC3A2sp|P08195-2|4F2_HUMAN 58 kDa 41 SLC3A2Guanine nucleotide-binding protein G(I) / G(S) / G(T) subunitbeta-1 OS=Homo sapiens OX=9606 |GNB1 PE=1 SV=3sp|P62873|GBB1_HUMAN 37 kDa 42 GNB1Myelin proteolipid protein OS=Homo sapiens OX=9606|PLP1 PE=1 SV=2sp|P60201|MYPR_HUMAN 30 kDa 43 PLP1Guanine nucleotide-binding protein G(i) subunit alpha-1OS=Homo sapiens OX=9606 |GNAI1 PE=1 SV=2sp|P63096|GNAI1_HUMAN 40 kDa 44 GNAI1ATP synthase subunit alpha, mitochondrial OS=Homosapiens OX=9606 |ATP5F1A PE=1 SV=1sp|P25705|ATPA_HUMAN 60 kDa 45 ATP5F1ASynaptotagmin-1 OS=Homo sapiens OX=9606 |SYT1 PE=1SV=1sp|P21579|SYT1_HUMAN 48 kDa 46 SYT1Pyruvate kinase PKM OS=Homo sapiens OX=9606 |PKMPE=1 SV=4sp|P14618|KPYM_HUMAN 58 kDa 47 PKMIsoform M1 of Pyruvate kinase PKM OS=Homo sapiensOX=9606 |PKMsp|P14618-2|KPYM_HUMAN 58 kDa 48 PKMContactin-associated protein 1 OS=Homo sapiens OX=9606|CNTNAP1 PE=1 SV=1sp|P78357|CNTP1_HUMAN 156 kDa 49 CNTNAP1Isoform XA of Plasma membrane calcium-transportingATPase 3 OS=Homo sapiens OX=9606 |ATP2B3sp|Q16720-2|AT2B3_HUMAN (+3) 129 kDa 50 ATP2B3Isoform 2 of Glial fibrillary acidic protein OS=Homo sapiensOX=9606 |GFAPsp|P14136-2|GFAP_HUMAN (+2) 50 kDa 51 GFAP

[0005] Attorney Docket No.07039-2255WO1 2022-307 Isoform DPPX-S of Dipeptidyl aminopeptidase-like protein6 OS=Homo sapiens OX=9606 |DPP6sp|P42658-2|DPP6_HUMAN 91 kDa 52 DPP6Isoform 2 of Spectrin alpha chain, non-erythrocytic 1OS=Homo sapiens OX=9606 |SPTAN1sp|Q13813-2|SPTN1_HUMAN 285 kDa 53 SPTAN1Spectrin beta chain, non-erythrocytic 1 OS=Homo sapiensOX=9606 |SPTBN1 PE=1 SV=2sp|Q01082|SPTB2_HUMAN 275 kDa 54 SPTBN1Epoxide hydrolase 1 OS=Homo sapiens OX=9606 |EPHX1PE=1 SV=1sp|P07099|HYEP_HUMAN 53 kDa 55 EPHX1ADP / ATP translocase 3 OS=Homo sapiens OX=9606|SLC25A6 PE=1 SV=4sp|P12236|ADT3_HUMAN 33 kDa 56 SLC25A6Isoform 2 of Calnexin OS=Homo sapiens OX=9606 |CANXsp|P27824-2|CALX_HUMAN (+1) 72 kDa 57 CANXNeural cell adhesion molecule 1 OS=Homo sapiensOX=9606 |NCAM1 PE=1 SV=3sp|P13591|NCAM1_HUMAN 95 kDa 58 NCAM1Sodium / potassium-transporting ATPase subunit beta-2OS=Homo sapiens OX=9606 |ATP1B2 PE=1 SV=3sp|P14415|AT1B2_HUMAN 33 kDa 59 ATP1B2Annexin A2 OS=Homo sapiens OX=9606 |ANXA2 PE=1SV=2sp|P07355|ANXA2_HUMAN 39 kDa 60 ANXA2Amine oxidase [flavin-containing] B OS=Homo sapiensOX=9606 |MAOB PE=1 SV=3sp|P27338|AOFB_HUMAN 59 kDa 61 MAOBCalcium-binding mitochondrial carrier protein Aralar1OS=Homo sapiens OX=9606 |SLC25A12 PE=1 SV=2sp|O75746|CMC1_HUMAN 75 kDa 62 SLC25A12Annexin A5 OS=Homo sapiens OX=9606 |ANXA5 PE=1SV=2sp|P08758|ANXA5_HUMAN 36 kDa 63 ANXA5Isoform 2 of Phospholipid-transporting ATPase IAOS=Homo sapiens OX=9606 |ATP8A1sp|Q9Y2Q0-2|AT8A1_HUMAN (+1) 130 kDa 64 ATP8A1ADP / ATP translocase 2 OS=Homo sapiens OX=9606|SLC25A5 PE=1 SV=7sp|P05141|ADT2_HUMAN 33 kDa 65 SLC25A5Isoform 2 of Syntaxin-1B OS=Homo sapiens OX=9606|STX1Bsp|P61266-2|STX1B_HUMAN (+1) 32 kDa 66 STX1BVoltage-dependent anion-selective channel protein 1OS=Homo sapiens OX=9606 |VDAC1 PE=1 SV=2sp|P21796|VDAC1_HUMAN 31 kDa 67 VDAC1ADP / ATP translocase 1 OS=Homo sapiens OX=9606|SLC25A4 PE=1 SV=4sp|P12235|ADT1_HUMAN 33 kDa 68 SLC25A4

[0006] Attorney Docket No.07039-2255WO1 2022-307 Guanine nucleotide-binding protein G(I) / G(S) / G(T) subunitbeta-2 OS=Homo sapiens OX=9606 |GNB2 PE=1 SV=3sp|P62879|GBB2_HUMAN 37 kDa 69 GNB2Flotillin-2 OS=Homo sapiens OX=9606 |FLOT2 PE=1 SV=2sp|Q14254|FLOT2_HUMAN 47 kDa 70 FLOT2Flotillin-1 OS=Homo sapiens OX=9606 |FLOT1 PE=1 SV=3sp|O75955|FLOT1_HUMAN 47 kDa 71 FLOT1Isoform 2 of Heat shock protein HSP 90-alpha OS=Homosapiens OX=9606 |HSP90AA1sp|P07900-2|HS90A_HUMAN 98 kDa 72 HSP90AA1Isoform 9 of Neurofascin OS=Homo sapiens OX=9606|NFASCsp|O94856-9|NFASC_HUMAN 138 kDa 73 NFASCHeat shock protein HSP 90-beta OS=Homo sapiensOX=9606 |HSP90AB1 PE=1 SV=4sp|P08238|HS90B_HUMAN 83 kDa 74 HSP90AB1Isoform B of Calcium / calmodulin-dependent protein kinase type II subunit alpha OS=Homo sapiens OX=9606 sp|Q9UQM7-2|KCC2A_HUMAN 55 kDa 75 CAMK2A|CAMK2A(+1)Sarcoplasmic / endoplasmic reticulum calcium ATPase 2OS=Homo sapiens OX=9606 |ATP2A2 PE=1 SV=1sp|P16615|AT2A2_HUMAN 115 kDa 76 ATP2A2Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas OS=Homo sapiens OX=9606 |GNAS PE=1 sp|Q5JWF2|GNAS1_HUMAN 111 kDa 77 GNAS SV=2 Heat shock cognate 71 kDa protein OS=Homo sapiensOX=9606 |HSPA8 PE=1 SV=1sp|P11142|HSP7C_HUMAN 71 kDa 78 HSPA8Vesicle-associated membrane protein 2 OS=Homo sapiensOX=9606 |VAMP2 PE=1 SV=3sp|P63027|VAMP2_HUMAN 13 kDa 79 VAMP2V-type proton ATPase subunit d 1 OS=Homo sapiensOX=9606 |ATP6V0D1 PE=1 SV=1sp|P61421|VA0D1_HUMAN 40 kDa 80 ATP6V0D1V-type proton ATPase subunit C 1 OS=Homo sapiensOX=9606 |ATP6V1C1 PE=1 SV=4sp|P21283|VATC1_HUMAN 44 kDa 81 ATP6V1C1Thy-1 membrane glycoprotein OS=Homo sapiens OX=9606|THY1 PE=1 SV=2sp|P04216|THY1_HUMAN 18 kDa 82 THY1Isoform 2 of V-type proton ATPase subunit H OS=Homosapiens OX=9606 |ATP6V1Hsp|Q9UI12-2|VATH_HUMAN (+1) 54 kDa 83 ATP6V1HHemoglobin subunit beta OS=Homo sapiens OX=9606|HBB PE=1 SV=2sp|P68871|HBB_HUMAN 16 kDa 84 HBB

[0007] Attorney Docket No.07039-2255WO1 2022-307 Ras-related protein Rab-1B OS=Homo sapiens OX=9606|RAB1B PE=1 SV=1sp|Q9H0U4|RAB1B_HUMAN 22 kDa 85 RAB1BHLA class II histocompatibility antigen, DRB1-1 beta chainOS=Homo sapiens OX=9606 |HLA-DRB1 PE=1 SV=2sp|P04229|2B11_HUMAN 30 kDa 86 HLA-DRB1Synaptophysin OS=Homo sapiens OX=9606 |SYP PE=1SV=3sp|P08247|SYPH_HUMAN 34 kDa 87 SYPIsoform 2 of NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial OS=Homo sapiens OX=9606 sp|P28331-2|NDUS1_HUMAN 81 kDa 88 NDUFS1 |NDUFS1 Alpha-enolase OS=Homo sapiens OX=9606 |ENO1 PE=1SV=2sp|P06733|ENOA_HUMAN 47 kDa 89 ENO1Cytochrome b-c1 complex subunit 1, mitochondrialOS=Homo sapiens OX=9606 |UQCRC1 PE=1 SV=3sp|P31930|QCR1_HUMAN 53 kDa 90 UQCRC1Isoform 4 of Neuroplastin OS=Homo sapiens OX=9606|NPTNsp|Q9Y639-4|NPTN_HUMAN (+2) 38 kDa 91 NPTNSyntaxin-1A OS=Homo sapiens OX=9606 |STX1A PE=1SV=1sp|Q16623|STX1A_HUMAN 33 kDa 92 STX1ABand 3 anion transport protein OS=Homo sapiens OX=9606|SLC4A1 PE=1 SV=3sp|P02730|B3AT_HUMAN 102 kDa 93 SLC4A1Prohibitin-2 OS=Homo sapiens OX=9606 |PHB2 PE=1SV=2sp|Q99623|PHB2_HUMAN 33 kDa 94 PHB2Isoform 2 of Neuronal membrane glycoprotein M6-aOS=Homo sapiens OX=9606 |GPM6Asp|P51674-2|GPM6A_HUMAN (+2) 30 kDa 95 GPM6ARas-related protein Rab-3A OS=Homo sapiens OX=9606|RAB3A PE=1 SV=1sp|P20336|RAB3A_HUMAN 25 kDa 96 RAB3AIsoform 2 of Pre-B-cell leukemia transcription factor-interacting protein 1 OS=Homo sapiens OX=9606 |PBXIP1sp|Q96AQ6-2|PBIP1_HUMAN (+1) 78 kDa 97 PBXIP1Tyrosine-protein phosphatase non-receptor type substrate 1OS=Homo sapiens OX=9606 |SIRPA PE=1 SV=2sp|P78324|SHPS1_HUMAN 55 kDa 98 SIRPAIsoform LCRMP-1 of Dihydropyrimidinase-related protein 1OS=Homo sapiens OX=9606 |CRMP1sp|Q14194-2|DPYL1_HUMAN (+1) 74 kDa 99 CRMP1ATP-dependent 6-phosphofructokinase, platelet typeOS=Homo sapiens OX=9606 |PFKP PE=1 SV=2sp|Q01813|PFKAP_HUMAN 86 kDa 100 PFKP

[0008] Attorney Docket No.07039-2255WO1 2022-307 V-type proton ATPase subunit E 1 OS=Homo sapiensOX=9606 |ATP6V1E1 PE=1 SV=1sp|P36543|VATE1_HUMAN 26 kDa 101 ATP6V1E1Fructose-bisphosphate aldolase C OS=Homo sapiensOX=9606 |ALDOC PE=1 SV=2sp|P09972|ALDOC_HUMAN 39 kDa 102 ALDOCGuanine nucleotide-binding protein subunit alpha-13OS=Homo sapiens OX=9606 |GNA13 PE=1 SV=2sp|Q14344|GNA13_HUMAN 44 kDa 103 GNA13Glutamate dehydrogenase 1, mitochondrial OS=Homosapiens OX=9606 |GLUD1 PE=1 SV=2sp|P00367|DHE3_HUMAN 61 kDa 104 GLUD1Alpha-crystallin B chain OS=Homo sapiens OX=9606|CRYAB PE=1 SV=2sp|P02511|CRYAB_HUMAN 20 kDa 105 CRYABHemoglobin subunit alpha OS=Homo sapiens OX=9606|HBA1 PE=1 SV=2sp|P69905|HBA_HUMAN 15 kDa 106 HBA1Isoform 1 of Voltage-dependent anion-selective channelprotein 2 OS=Homo sapiens OX=9606 |VDAC2sp|P45880-1|VDAC2_HUMAN (+1) 33 kDa 107 VDAC214-3-3 protein epsilon OS=Homo sapiens OX=9606|YWHAE PE=1 SV=1sp|P62258|1433E_HUMAN 29 kDa 108 YWHAEIsoform 4 of Dynamin-3 OS=Homo sapiens OX=9606|DNM3sp|Q9UQ16-4|DYN3_HUMAN (+1) 98 kDa 109 DNM3Rab GDP dissociation inhibitor alpha OS=Homo sapiensOX=9606 |GDI1 PE=1 SV=2sp|P31150|GDIA_HUMAN 51 kDa 110 GDI1Isoform 2 of Opioid-binding protein / cell adhesion moleculeOS=Homo sapiens OX=9606 |OPCMLsp|Q14982-2|OPCM_HUMAN (+3) 37 kDa 111 OPCMLGuanine nucleotide-binding protein G(q) subunit alphaOS=Homo sapiens OX=9606 |GNAQ PE=1 SV=4sp|P50148|GNAQ_HUMAN 42 kDa 112 GNAQVisinin-like protein 1 OS=Homo sapiens OX=9606 |VSNL1PE=1 SV=2sp|P62760|VISL1_HUMAN 22 kDa 113 VSNL1Isoform 5 of Electrogenic sodium bicarbonate cotransporter1 OS=Homo sapiens OX=9606 |SLC4A4sp|Q9Y6R1-5|S4A4_HUMAN 123 kDa 114 SLC4A4Inactive dipeptidyl peptidase 10 OS=Homo sapiensOX=9606 |DPP10 PE=1 SV=2sp|Q8N608|DPP10_HUMAN 91 kDa 115 DPP10NAD(P) transhydrogenase, mitochondrial OS=Homo sapiensOX=9606 |NNT PE=1 SV=3sp|Q13423|NNTM_HUMAN 114 kDa 116 NNT

[0009] Attorney Docket No.07039-2255WO1 2022-307 Neutral amino acid transporter A OS=Homo sapiensOX=9606 |SLC1A4 PE=1 SV=1sp|P43007|SATT_HUMAN 56 kDa 117 SLC1A4Ras-related C3 botulinum toxin substrate 1 OS=Homosapiens OX=9606 |RAC1 PE=1 SV=1sp|P63000|RAC1_HUMAN 21 kDa 118 RAC1Elongation factor 1-alpha 1 OS=Homo sapiens OX=9606|EEF1A1 PE=1 SV=1sp|P68104|EF1A1_HUMAN (+1) 50 kDa 119 EEF1A1Isoform 2 of Band 4.1-like protein 3 OS=Homo sapiensOX=9606 |EPB41L3sp|Q9Y2J2-2|E41L3_HUMAN 97 kDa 120 EPB41L3Dihydropyrimidinase-related protein 3 OS=Homo sapiensOX=9606 |DPYSL3 PE=1 SV=1sp|Q14195|DPYL3_HUMAN 62 kDa 121 DPYSL3Myelin-oligodendrocyte glycoprotein OS=Homo sapiensOX=9606 |MOG PE=1 SV=2sp|Q16653|MOG_HUMAN 28 kDa 122 MOGMyelin basic protein OS=Homo sapiens OX=9606 |MBPPE=1 SV=3sp|P02686|MBP_HUMAN 33 kDa 123 MBPIsoform 2 of Voltage-dependent anion-selective channelprotein 3 OS=Homo sapiens OX=9606 |VDAC3sp|Q9Y277-2|VDAC3_HUMAN (+1) 31 kDa 124 VDAC3L-lactate dehydrogenase B chain OS=Homo sapiensOX=9606 |LDHB PE=1 SV=2sp|P07195|LDHB_HUMAN 37 kDa 125 LDHBIsoform 2 of NADH-cytochrome b5 reductase 3 OS=Homosapiens OX=9606 |CYB5R3sp|P00387-2|NB5R3_HUMAN (+2) 32 kDa 126 CYB5R3Fructose-bisphosphate aldolase A OS=Homo sapiensOX=9606 |ALDOA PE=1 SV=2sp|P04075|ALDOA_HUMAN 39 kDa 127 ALDOAIsoform 2 of Basigin OS=Homo sapiens OX=9606 |BSGsp|P35613-2|BASI_HUMAN (+1) 29 kDa 128 BSGPeroxiredoxin-1 OS=Homo sapiens OX=9606 |PRDX1PE=1 SV=1sp|Q06830|PRDX1_HUMAN 22 kDa 129 PRDX1Cytochrome b-c1 complex subunit 2, mitochondrialOS=Homo sapiens OX=9606 |UQCRC2 PE=1 SV=3sp|P22695|QCR2_HUMAN 48 kDa 130 UQCRC2Gamma-enolase OS=Homo sapiens OX=9606 |ENO2 PE=1SV=3sp|P09104|ENOG_HUMAN 47 kDa 131 ENO2Guanine nucleotide-binding protein subunit alpha-11OS=Homo sapiens OX=9606 |GNA11 PE=1 SV=2sp|P29992|GNA11_HUMAN 42 kDa 132 GNA11Neural cell adhesion molecule 2 OS=Homo sapiensOX=9606 |NCAM2 PE=1 SV=2sp|O15394|NCAM2_HUMAN 93 kDa 133 NCAM2

[0010] Attorney Docket No.07039-2255WO1 2022-307 Isoform 2 of Myosin-10 OS=Homo sapiens OX=9606|MYH10sp|P35580-2|MYH10_HUMAN (+4) 231 kDa 134 MYH10Isoform 1 of Calcium / calmodulin-dependent protein kinasetype II subunit beta OS=Homo sapiens OX=9606 |CAMK2Bsp|Q13554-2|KCC2B_HUMAN (+1) 60 kDa 135 CAMK2BATP synthase subunit O, mitochondrial OS=Homo sapiensOX=9606 |ATP5PO PE=1 SV=1sp|P48047|ATPO_HUMAN 23 kDa 136 ATP5POIsoform 2 of Synaptic vesicle glycoprotein 2A OS=Homosapiens OX=9606 |SV2Asp|Q7L0J3-2|SV2A_HUMAN (+1) 77 kDa 137 SV2AdCas9_mCherry_APEX2dCas9_mCherry_APEX2 234 kDa 138Isoform IB of Synapsin-1 OS=Homo sapiens OX=9606|SYN1sp|P17600-2|SYN1_HUMAN (+1) 70 kDa 139 SYN1Isoform B of AP-2 complex subunit alpha-1 OS=Homosapiens OX=9606 |AP2A1sp|O95782-2|AP2A1_HUMAN (+1) 105 kDa 140 AP2A1Isoform 3 of ATP-dependent 6-phosphofructokinase, muscletype OS=Homo sapiens OX=9606 |PFKMsp|P08237-3|PFKAM_HUMAN (+1) 93 kDa 141 PFKMIsoform 2 of AP-2 complex subunit beta OS=Homo sapiensOX=9606 |AP2B1sp|P63010-2|AP2B1_HUMAN (+1) 106 kDa 142 AP2B1CD81 antigen OS=Homo sapiens OX=9606 |CD81 PE=1SV=1sp|P60033|CD81_HUMAN 26 kDa 143 CD81Heat shock 70 kDa protein 12A OS=Homo sapiensOX=9606 |HSPA12A PE=1 SV=2sp|O43301|HS12A_HUMAN 75 kDa 144 HSPA12AATP-dependent 6-phosphofructokinase, liver typeOS=Homo sapiens OX=9606 |PFKL PE=1 SV=6sp|P17858|PFKAL_HUMAN 85 kDa 145 PFKLPhosphoglycerate kinase 1 OS=Homo sapiens OX=9606|PGK1 PE=1 SV=3sp|P00558|PGK1_HUMAN 45 kDa 146 PGK1Aspartate aminotransferase, cytoplasmic OS=Homo sapiensOX=9606 |GOT1 PE=1 SV=3sp|P17174|AATC_HUMAN 46 kDa 147 GOT1Vesicular glutamate transporter 1 OS=Homo sapiensOX=9606 |SLC17A7 PE=2 SV=1sp|Q9P2U7|VGLU1_HUMAN 62 kDa 148 SLC17A7CD9 antigen OS=Homo sapiens OX=9606 |CD9 PE=1 SV=4sp|P21926|CD9_HUMAN 25 kDa 149 CD9Ectonucleotide pyrophosphatase / phosphodiesterase familymember 6 OS=Homo sapiens OX=9606 |ENPP6 PE=1 SV=2sp|Q6UWR7|ENPP6_HUMAN 50 kDa 151 ENPP6

[0011] Attorney Docket No.07039-2255WO1 2022-307 Erythrocyte band 7 integral membrane protein OS=Homosapiens OX=9606 |STOM PE=1 SV=3sp|P27105|STOM_HUMAN 32 kDa 152 STOMADP-ribosylation factor 3 OS=Homo sapiens OX=9606|ARF3 PE=1 SV=2sp|P61204|ARF3_HUMAN (+1) 21 kDa 153 ARF3Sodium / calcium exchanger 2 OS=Homo sapiens OX=9606|SLC8A2 PE=2 SV=2sp|Q9UPR5|NAC2_HUMAN 100 kDa 154 SLC8A2Glycogen phosphorylase, brain form OS=Homo sapiensOX=9606 |PYGB PE=1 SV=5sp|P11216|PYGB_HUMAN 97 kDa 155 PYGBPeroxiredoxin-2 OS=Homo sapiens OX=9606 |PRDX2PE=1 SV=5sp|P32119|PRDX2_HUMAN 22 kDa 156 PRDX2Ras-related protein Rab-14 OS=Homo sapiens OX=9606|RAB14 PE=1 SV=4sp|P61106|RAB14_HUMAN 24 kDa 157 RAB14Prohibitin OS=Homo sapiens OX=9606 |PHB PE=1 SV=1sp|P35232|PHB_HUMAN 30 kDa 158 PHBSideroflexin-1 OS=Homo sapiens OX=9606 |SFXN1 PE=1SV=4sp|Q9H9B4|SFXN1_HUMAN 36 kDa 159 SFXN1Phospholipid phosphatase 3 OS=Homo sapiens OX=9606|PLPP3 PE=1 SV=1sp|O14495|PLPP3_HUMAN 35 kDa 160 PLPP3Mitochondrial 2-oxoglutarate / malate carrier proteinOS=Homo sapiens OX=9606 |SLC25A11 PE=1 SV=3sp|Q02978|M2OM_HUMAN 34 kDa 161 SLC25A11Elongation factor 1-alpha 2 OS=Homo sapiens OX=9606|EEF1A2 PE=1 SV=1sp|Q05639|EF1A2_HUMAN 50 kDa 162 EEF1A2Leukocyte surface antigen CD47 OS=Homo sapiensOX=9606 |CD47 PE=1 SV=1sp|Q08722|CD47_HUMAN 35 kDa 163 CD47Ras-related protein Rap-2a OS=Homo sapiens OX=9606|RAP2A PE=1 SV=1sp|P10114|RAP2A_HUMAN 21 kDa 164 RAP2ATenascin-R OS=Homo sapiens OX=9606 |TNR PE=1 SV=3sp|Q92752|TENR_HUMAN 150 kDa 165 TNRIsoform 2 of Protein tweety homolog 1 OS=Homo sapiensOX=9606 |TTYH1sp|Q9H313-2|TTYH1_HUMAN (+1) 49 kDa 166 TTYH1V-type proton ATPase subunit D OS=Homo sapiensOX=9606 |ATP6V1D PE=1 SV=1sp|Q9Y5K8|VATD_HUMAN 28 kDa 167 ATP6V1DIsoform 2 of Voltage-dependent calcium channel subunitalpha-2 / delta-1 OS=Homo sapiens OX=9606 |CACNA2D1sp|P54289-2|CA2D1_HUMAN (+1) 123 kDa 168 CACNA2D1

[0012] Attorney Docket No.07039-2255WO1 2022-307 Versican core protein OS=Homo sapiens OX=9606 |VCANPE=1 SV=3sp|P13611|CSPG2_HUMAN 373 kDa 169 VCANBeta-2-glycoprotein 1 OS=Homo sapiens OX=9606 |APOHPE=1 SV=3sp|P02749|APOH_HUMAN 38 kDa 170 APOHCofilin-1 OS=Homo sapiens OX=9606 |CFL1 PE=1 SV=3sp|P23528|COF1_HUMAN 19 kDa 171 CFL114-3-3 protein gamma OS=Homo sapiens OX=9606|YWHAG PE=1 SV=2sp|P61981|1433G_HUMAN 28 kDa 172 YWHAGTriosephosphate isomerase OS=Homo sapiens OX=9606|TPI1 PE=1 SV=3sp|P60174|TPIS_HUMAN 31 kDa 173 TPI1Isoform 2 of Choline transporter-like protein 2 OS=Homosapiens OX=9606 |SLC44A2sp|Q8IWA5-2|CTL2_HUMAN (+2) 81 kDa 174 SLC44A2Erlin-2 OS=Homo sapiens OX=9606 |ERLIN2 PE=1 SV=1sp|O94905|ERLN2_HUMAN 38 kDa 175 ERLIN2Brain acid soluble protein 1 OS=Homo sapiens OX=9606|BASP1 PE=1 SV=2sp|P80723|BASP1_HUMAN 23 kDa 176 BASP1Trifunctional enzyme subunit alpha, mitochondrialOS=Homo sapiens OX=9606 |HADHA PE=1 SV=2sp|P40939|ECHA_HUMAN 83 kDa 177 HADHAIsoform Delta 10 of Calcium / calmodulin-dependent protein kinase type II subunit delta OS=Homo sapiens OX=9606 sp|Q13557-10|KCC2D_HUMAN (+7) 56 kDa 178 CAMK2D |CAMK2D Isoform 2 of Neural cell adhesion molecule L1 OS=Homosapiens OX=9606 |L1CAMsp|P32004-2|L1CAM_HUMAN (+2) 140 kDa 179 L1CAMMyosin-9 OS=Homo sapiens OX=9606 |MYH9 PE=1 SV=4sp|P35579|MYH9_HUMAN 227 kDa 180 MYH914-3-3 protein zeta / delta OS=Homo sapiens OX=9606|YWHAZ PE=1 SV=1sp|P63104|1433Z_HUMAN 28 kDa 181 YWHAZRab GDP dissociation inhibitor beta OS=Homo sapiensOX=9606 |GDI2 PE=1 SV=2sp|P50395|GDIB_HUMAN 51 kDa 182 GDI2Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 3OS=Homo sapiens OX=9606 |HACD3 PE=1 SV=2sp|Q9P035|HACD3_HUMAN 43 kDa 183 HACD3Protein kinase C gamma type OS=Homo sapiens OX=9606|PRKCG PE=1 SV=3sp|P05129|KPCG_HUMAN 78 kDa 184 PRKCGMicrotubule-associated protein 1B OS=Homo sapiensOX=9606 |MAP1B PE=1 SV=2sp|P46821|MAP1B_HUMAN 271 kDa 185 MAP1B

[0013] Attorney Docket No.07039-2255WO1 2022-307 L-lactate dehydrogenase A chain OS=Homo sapiensOX=9606 |LDHA PE=1 SV=2sp|P00338|LDHA_HUMAN 37 kDa 186 LDHACarbonyl reductase [NADPH] 1 OS=Homo sapiensOX=9606 |CBR1 PE=1 SV=3sp|P16152|CBR1_HUMAN 30 kDa 187 CBR1Isoform 2 of Neurochondrin OS=Homo sapiens OX=9606|NCDNsp|Q9UBB6-2|NCDN_HUMAN (+2) 77 kDa 188 NCDNIsoform 2 of Ras-related protein Rab-6A OS=Homo sapiensOX=9606 |RAB6Asp|P20340-2|RAB6A_HUMAN (+1) 24 kDa 189 RAB6AADP-ribosylation factor 4 OS=Homo sapiens OX=9606|ARF4 PE=1 SV=3sp|P18085|ARF4_HUMAN 21 kDa 190 ARF4Isoform 2 of AP-2 complex subunit alpha-2 OS=Homosapiens OX=9606 |AP2A2sp|O94973-2|AP2A2_HUMAN (+1) 104 kDa 191 AP2A2Isoform 2 of Synaptoporin OS=Homo sapiens OX=9606|SYNPRsp|Q8TBG9-2|SYNPR_HUMAN 31 kDa 192 SYNPRProtein-arginine deiminase type-2 OS=Homo sapiensOX=9606 |PADI2 PE=1 SV=2sp|Q9Y2J8|PADI2_HUMAN 76 kDa 193 PADI2Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 OS=Homo sapiens OX=9606 sp|P04843|RPN1_HUMAN 69 kDa 194 RPN1 |RPN1 PE=1 SV=1 Hyaluronan and proteoglycan link protein 2 OS=Homosapiens OX=9606 |HAPLN2 PE=2 SV=1sp|Q9GZV7|HPLN2_HUMAN 38 kDa 195 HAPLN2Transitional endoplasmic reticulum ATPase OS=Homosapiens OX=9606 |VCP PE=1 SV=4sp|P55072|TERA_HUMAN 89 kDa 196 VCPPeptidyl-prolyl cis-trans isomerase A OS=Homo sapiensOX=9606 |PPIA PE=1 SV=2sp|P62937|PPIA_HUMAN 18 kDa 197 PPIAUbiquitin-like modifier-activating enzyme 1 OS=Homosapiens OX=9606 |UBA1 PE=1 SV=3sp|P22314|UBA1_HUMAN 118 kDa 198 UBA1Glucose-6-phosphate isomerase OS=Homo sapiensOX=9606 |GPI PE=1 SV=4sp|P06744|G6PI_HUMAN 63 kDa 199 GPIZinc transporter 3 OS=Homo sapiens OX=9606 |SLC30A3PE=1 SV=2sp|Q99726|ZNT3_HUMAN 42 kDa 200 SLC30A3Saccharopine dehydrogenase-like oxidoreductase OS=Homosapiens OX=9606 |SCCPDH PE=1 SV=1sp|Q8NBX0|SCPDL_HUMAN 47 kDa 201 SCCPDH

[0014] Attorney Docket No.07039-2255WO1 2022-307 Isoform 2 of Secretory carrier-associated membrane protein5 OS=Homo sapiens OX=9606 |SCAMP5sp|Q8TAC9-2|SCAM5_HUMAN (+1) 27 kDa 202 SCAMP5Isoform 2 of Choline transporter-like protein 1 OS=Homosapiens OX=9606 |SLC44A1sp|Q8WWI5-2|CTL1_HUMAN (+2) 73 kDa 203 SLC44A1Amine oxidase [flavin-containing] A OS=Homo sapiensOX=9606 |MAOA PE=1 SV=1sp|P21397|AOFA_HUMAN 60 kDa 204 MAOARas-related protein Rap-2b OS=Homo sapiens OX=9606|RAP2B PE=1 SV=1sp|P61225|RAP2B_HUMAN 21 kDa 205 RAP2BProtein MAL2 OS=Homo sapiens OX=9606 |MAL2 PE=1SV=1sp|Q969L2|MAL2_HUMAN 19 kDa 206 MAL2Neuronal growth regulator 1 OS=Homo sapiens OX=9606|NEGR1 PE=1 SV=3sp|Q7Z3B1|NEGR1_HUMAN 39 kDa 207 NEGR1Isoform 2 of NAD-dependent protein deacetylase sirtuin-2OS=Homo sapiens OX=9606 |SIRT2sp|Q8IXJ6-2|SIR2_HUMAN (+2) 40 kDa 208 SIRT2Isoform Heart of ATP synthase subunit gamma,mitochondrial OS=Homo sapiens OX=9606 |ATP5F1Csp|P36542-2|ATPG_HUMAN (+1) 33 kDa 209 ATP5F1CSideroflexin-3 OS=Homo sapiens OX=9606 |SFXN3 PE=1SV=3sp|Q9BWM7|SFXN3_HUMAN 36 kDa 210 SFXN3Malate dehydrogenase, mitochondrial OS=Homo sapiensOX=9606 |MDH2 PE=1 SV=3sp|P40926|MDHM_HUMAN 36 kDa 211 MDH2Aquaporin-4 OS=Homo sapiens OX=9606 |AQP4 PE=1SV=2sp|P55087|AQP4_HUMAN 35 kDa 212 AQP4Isoform 2 of Cytoplasmic FMR1-interacting protein 2OS=Homo sapiens OX=9606 |CYFIP2sp|Q96F07-2|CYFP2_HUMAN 146 kDa 213 CYFIP2Annexin A1 OS=Homo sapiens OX=9606 |ANXA1 PE=1SV=2sp|P04083|ANXA1_HUMAN 39 kDa 214 ANXA1Heat shock 70 kDa protein 1B OS=Homo sapiens OX=9606|HSPA1B PE=1 SV=1sp|P0DMV9|HS71B_HUMAN 70 kDa 215 HSPA1BProtein kinase C alpha type OS=Homo sapiens OX=9606|PRKCA PE=1 SV=4sp|P17252|KPCA_HUMAN 77 kDa 216 PRKCAMalate dehydrogenase, cytoplasmic OS=Homo sapiensOX=9606 |MDH1 PE=1 SV=4sp|P40925|MDHC_HUMAN 36 kDa 217 MDH1

[0015] Attorney Docket No.07039-2255WO1 2022-307 Cytochrome c oxidase subunit 4 isoform 1, mitochondrialOS=Homo sapiens OX=9606 |COX4I1 PE=1 SV=1sp|P13073|COX41_HUMAN 20 kDa 218 COX4I1Cytochrome c oxidase subunit 5A, mitochondrial OS=Homosapiens OX=9606 |COX5A PE=1 SV=2sp|P20674|COX5A_HUMAN 17 kDa 219 COX5ARho-related GTP-binding protein RhoB OS=Homo sapiensOX=9606 |RHOB PE=1 SV=1sp|P62745|RHOB_HUMAN 22 kDa 220 RHOB40S ribosomal protein S3 OS=Homo sapiens OX=9606|RPS3 PE=1 SV=2sp|P23396|RS3_HUMAN 27 kDa 221 RPS3Isoform 2 of Cell adhesion molecule 3 OS=Homo sapiensOX=9606 |CADM3sp|Q8N126-2|CADM3_HUMAN (+1) 47 kDa 222 CADM3Ras-related protein Ral-A OS=Homo sapiens OX=9606|RALA PE=1 SV=1sp|P11233|RALA_HUMAN 24 kDa 223 RALAPeroxiredoxin-6 OS=Homo sapiens OX=9606 |PRDX6PE=1 SV=3sp|P30041|PRDX6_HUMAN 25 kDa 224 PRDX6Protein kinase C beta type OS=Homo sapiens OX=9606|PRKCB PE=1 SV=4sp|P05771|KPCB_HUMAN 77 kDa 225 PRKCBIsoform 4 of Ankyrin-2 OS=Homo sapiens OX=9606 |ANK2sp|Q01484-5|ANK2_HUMAN 205 kDa 226 ANK2Glutathione S-transferase Mu 3 OS=Homo sapiens OX=9606|GSTM3 PE=1 SV=3sp|P21266|GSTM3_HUMAN 27 kDa 227 GSTM3Phosphoglycerate mutase 1 OS=Homo sapiens OX=9606|PGAM1 PE=1 SV=2sp|P18669|PGAM1_HUMAN 29 kDa 228 PGAM1Endoplasmin OS=Homo sapiens OX=9606 |HSP90B1 PE=1SV=1sp|P14625|ENPL_HUMAN 92 kDa 229 HSP90B1Isoform 2 of Cell adhesion molecule 2 OS=Homo sapiensOX=9606 |CADM2sp|Q8N3J6-2|CADM2_HUMAN (+4) 44 kDa 230 CADM2Leucine-rich glioma-inactivated protein 1 OS=Homo sapiensOX=9606 |LGI1 PE=1 SV=1sp|O95970|LGI1_HUMAN 64 kDa 231 LGI1Isoform 2 of NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial OS=Homo sapiens OX=9606 sp|O75306-2|NDUS2_HUMAN (+1) 52 kDa 232 NDUFS2 |NDUFS2 Isoform 2 of Peroxiredoxin-like 2A OS=Homo sapiensOX=9606 |PRXL2Asp|Q9BRX8-2|PXL2A_HUMAN (+1) 24 kDa 233 PRXL2A

[0016] Attorney Docket No.07039-2255WO1 2022-307 Lysosome membrane protein 2 OS=Homo sapiens OX=9606|SCARB2 PE=1 SV=2sp|Q14108|SCRB2_HUMAN 54 kDa 234 SCARB2Guanine nucleotide-binding protein G(z) subunit alphaOS=Homo sapiens OX=9606 |GNAZ PE=1 SV=3sp|P19086|GNAZ_HUMAN 41 kDa 235 GNAZIsoform B of Phosphate carrier protein, mitochondrialOS=Homo sapiens OX=9606 |SLC25A3sp|Q00325-2|MPCP_HUMAN (+1) 40 kDa 236 SLC25A3Ferritin heavy chain OS=Homo sapiens OX=9606 |FTH1PE=1 SV=2sp|P02794|FRIH_HUMAN 21 kDa 237 FTH1Synapsin-2 OS=Homo sapiens OX=9606 |SYN2 PE=2 SV=4sp|Q92777|SYN2_HUMAN 63 kDa 238 SYN2Phosphatidylethanolamine-binding protein 1 OS=Homosapiens OX=9606 |PEBP1 PE=1 SV=3sp|P30086|PEBP1_HUMAN 21 kDa 239 PEBP1Mitochondrial carrier homolog 2 OS=Homo sapiensOX=9606 |MTCH2 PE=1 SV=1sp|Q9Y6C9|MTCH2_HUMAN 33 kDa 240 MTCH2Ras-related protein Rab-2A OS=Homo sapiens OX=9606|RAB2A PE=1 SV=1sp|P61019|RAB2A_HUMAN 24 kDa 241 RAB2AEndoplasmic reticulum chaperone BiP OS=Homo sapiensOX=9606 |HSPA5 PE=1 SV=2sp|P11021|BIP_HUMAN 72 kDa 242 HSPA5Ras-related protein Rap-1A OS=Homo sapiens OX=9606|RAP1A PE=1 SV=1sp|P62834|RAP1A_HUMAN 21 kDa 243 RAP1ASodium- and chloride-dependent GABA transporter 1OS=Homo sapiens OX=9606 |SLC6A1 PE=1 SV=2sp|P30531|SC6A1_HUMAN 67 kDa 244 SLC6A1Very-long-chain 3-oxoacyl-CoA reductase OS=Homosapiens OX=9606 |HSD17B12 PE=1 SV=2sp|Q53GQ0|DHB12_HUMAN 34 kDa 245 HSD17B12Trifunctional enzyme subunit beta, mitochondrial OS=Homosapiens OX=9606 |HADHB PE=1 SV=3sp|P55084|ECHB_HUMAN 51 kDa 246 HADHBSeptin-11 OS=Homo sapiens OX=9606 |SEPT11 PE=1SV=3sp|Q9NVA2|SEP11_HUMAN 49 kDa 247 SEPT11Septin-7 OS=Homo sapiens OX=9606 |SEPT7 PE=1 SV=2sp|Q16181|SEPT7_HUMAN 51 kDa 248 SEPT7Potassium voltage-gated channel subfamily A member 2OS=Homo sapiens OX=9606 |KCNA2 PE=1 SV=2sp|P16389|KCNA2_HUMAN 57 kDa 249 KCNA2V-type proton ATPase subunit G 2 OS=Homo sapiensOX=9606 |ATP6V1G2 PE=1 SV=1sp|O95670|VATG2_HUMAN 14 kDa 250 ATP6V1G2

[0017] Attorney Docket No.07039-2255WO1 2022-307 Cytochrome b-c1 complex subunit Rieske, mitochondrialOS=Homo sapiens OX=9606 |UQCRFS1 PE=1 SV=2sp|P47985|UCRI_HUMAN 30 kDa 251 UQCRFS1Isoform 2 of Serine / threonine-protein phosphatase 2B catalytic subunit alpha isoform OS=Homo sapiens OX=9606 sp|Q08209-2|PP2BA_HUMAN (+1) 58 kDa 252 PPP3CA |PPP3CA Isoform 2 of Neuronal cell adhesion molecule OS=Homosapiens OX=9606 |NRCAMsp|Q92823-2|NRCAM_HUMAN (+2) 137 kDa 253 NRCAMCreatine kinase U-type, mitochondrial OS=Homo sapiensOX=9606 |CKMT1A PE=1 SV=1sp|P12532|KCRU_HUMAN 47 kDa 254 CKMT1AD-3-phosphoglycerate dehydrogenase OS=Homo sapiensOX=9606 |PHGDH PE=1 SV=4sp|O43175|SERA_HUMAN 57 kDa 255 PHGDHIsoform 3 of Unconventional myosin-Va OS=Homo sapiensOX=9606 |MYO5Asp|Q9Y4I1-3|MYO5A_HUMAN 219 kDa 256 MYO5AAldehyde dehydrogenase, mitochondrial OS=Homo sapiensOX=9606 |ALDH2 PE=1 SV=2sp|P05091|ALDH2_HUMAN 56 kDa 257 ALDH2Transforming protein RhoA OS=Homo sapiens OX=9606|RHOA PE=1 SV=1sp|P61586|RHOA_HUMAN 22 kDa 258 RHOAIsoform Short of 14-3-3 protein beta / alpha OS=Homosapiens OX=9606 |YWHABsp|P31946-2|1433B_HUMAN (+1) 28 kDa 259 YWHABSynaptic vesicle glycoprotein 2B OS=Homo sapiensOX=9606 |SV2B PE=1 SV=1sp|Q7L1I2|SV2B_HUMAN 77 kDa 260 SV2BPRA1 family protein 3 OS=Homo sapiens OX=9606|ARL6IP5 PE=1 SV=1sp|O75915|PRAF3_HUMAN 22 kDa 261 ARL6IP5Endonuclease domain-containing 1 protein OS=Homosapiens OX=9606 |ENDOD1 PE=1 SV=2sp|O94919|ENDD1_HUMAN 55 kDa 262 ENDOD1Isoform 3 of Vesicle-associated membrane protein 1OS=Homo sapiens OX=9606 |VAMP1sp|P23763-2|VAMP1_HUMAN (+2) 13 kDa 263 VAMP1Isoform 2B of GTPase KRas OS=Homo sapiens OX=9606|KRASsp|P01116-2|RASK_HUMAN 21 kDa 264 KRASIsoform 2 of Adipocyte plasma membrane-associated protein sp|Q9HDC9-2|APMAP_HUMAN OS=Homo sapiens OX=9606 |APMAP(+1)32 kDa 265 APMAPGlycerol-3-phosphate dehydrogenase, mitochondrialOS=Homo sapiens OX=9606 |GPD2 PE=1 SV=3sp|P43304|GPDM_HUMAN 81 kDa 266 GPD2

[0018] Attorney Docket No.07039-2255WO1 2022-307 EH domain-containing protein 3 OS=Homo sapiensOX=9606 |EHD3 PE=1 SV=2sp|Q9NZN3|EHD3_HUMAN 61 kDa 267 EHD314-3-3 protein eta OS=Homo sapiens OX=9606 |YWHAHPE=1 SV=4sp|Q04917|1433F_HUMAN 28 kDa 268 YWHAH14-3-3 protein theta OS=Homo sapiens OX=9606 |YWHAQPE=1 SV=1sp|P27348|1433T_HUMAN 28 kDa 269 YWHAQIsoform 5 of CD44 antigen OS=Homo sapiens OX=9606|CD44sp|P16070-5|CD44_HUMAN (+4) 81 kDa 270 CD44Sodium- and chloride-dependent GABA transporter 3OS=Homo sapiens OX=9606 |SLC6A11 PE=2 SV=1sp|P48066|S6A11_HUMAN 71 kDa 271 SLC6A11V-type proton ATPase subunit S1 OS=Homo sapiensOX=9606 |ATP6AP1 PE=1 SV=2sp|Q15904|VAS1_HUMAN 52 kDa 272 ATP6AP1Mitochondrial glutamate carrier 1 OS=Homo sapiensOX=9606 |SLC25A22 PE=1 SV=1sp|Q9H936|GHC1_HUMAN 34 kDa 273 SLC25A22Cytochrome c oxidase subunit 2 OS=Homo sapiensOX=9606 |MT-CO2 PE=1 SV=1sp|P00403|COX2_HUMAN 26 kDa 274 MT-CO2Volume-regulated anion channel subunit LRRC8AOS=Homo sapiens OX=9606 |LRRC8A PE=1 SV=1sp|Q8IWT6|LRC8A_HUMAN 94 kDa 275 LRRC8ANADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial OS=Homo sapiens OX=9606 |NDUFV1 PE=1 sp|P49821|NDUV1_HUMAN 51 kDa 276 NDUFV1 SV=4 Elongation factor 2 OS=Homo sapiens OX=9606 |EEF2PE=1 SV=4sp|P13639|EF2_HUMAN 95 kDa 277 EEF2Methyltransferase-like protein 7A OS=Homo sapiensOX=9606 |METTL7A PE=1 SV=1sp|Q9H8H3|MET7A_HUMAN 28 kDa 278 METTL7AMitogen-activated protein kinase 1 OS=Homo sapiensOX=9606 |MAPK1 PE=1 SV=3sp|P28482|MK01_HUMAN 41 kDa 279 MAPK1Desmoplakin OS=Homo sapiens OX=9606 |DSP PE=1SV=3sp|P15924|DESP_HUMAN 332 kDa 280 DSPIsoform 2 of Annexin A7 OS=Homo sapiens OX=9606|ANXA7sp|P20073-2|ANXA7_HUMAN (+1) 50 kDa 281 ANXA7Transketolase OS=Homo sapiens OX=9606 |TKT PE=1SV=3sp|P29401|TKT_HUMAN 68 kDa 282 TKT

[0019] Attorney Docket No.07039-2255WO1 2022-307 Aconitate hydratase, mitochondrial OS=Homo sapiensOX=9606 |ACO2 PE=1 SV=2sp|Q99798|ACON_HUMAN 85 kDa 283 ACO2Copine-5 OS=Homo sapiens OX=9606 |CPNE5 PE=1 SV=2sp|Q9HCH3|CPNE5_HUMAN 66 kDa 284 CPNE5Isoform 2 of Ras-related protein Rab-5A OS=Homo sapiensOX=9606 |RAB5Asp|P20339-2|RAB5A_HUMAN (+1) 22 kDa 285 RAB5ACytochrome c oxidase subunit 7A2, mitochondrialOS=Homo sapiens OX=9606 |COX7A2 PE=1 SV=1sp|P14406|CX7A2_HUMAN 9 kDa 286 COX7A2Cytochrome c1, heme protein, mitochondrial OS=Homosapiens OX=9606 |CYC1 PE=1 SV=3sp|P08574|CY1_HUMAN 35 kDa 287 CYC1Heat shock protein beta-1 OS=Homo sapiens OX=9606|HSPB1 PE=1 SV=2sp|P04792|HSPB1_HUMAN 23 kDa 288 HSPB1Adenosylhomocysteinase OS=Homo sapiens OX=9606|AHCY PE=1 SV=4sp|P23526|SAHH_HUMAN 48 kDa 289 AHCYMetallo-beta-lactamase domain-containing protein 2OS=Homo sapiens OX=9606 |MBLAC2 PE=1 SV=3sp|Q68D91|MBLC2_HUMAN 31 kDa 290 MBLAC2Beta-soluble NSF attachment protein OS=Homo sapiensOX=9606 |NAPB PE=1 SV=2sp|Q9H115|SNAB_HUMAN 34 kDa 291 NAPBIsoform 2 of Annexin A11 OS=Homo sapiens OX=9606|ANXA11sp|P50995-2|ANX11_HUMAN (+1) 51 kDa 292 ANXA11Protein disulfide-isomerase A3 OS=Homo sapiens OX=9606|PDIA3 PE=1 SV=4sp|P30101|PDIA3_HUMAN 57 kDa 293 PDIA3Cullin-associated NEDD8-dissociated protein 1 OS=Homosapiens OX=9606 |CAND1 PE=1 SV=2sp|Q86VP6|CAND1_HUMAN 136 kDa 294 CAND1GTP-binding nuclear protein Ran OS=Homo sapiensOX=9606 |RAN PE=1 SV=3sp|P62826|RAN_HUMAN 24 kDa 295 RANKelch repeat and BTB domain-containing protein 11OS=Homo sapiens OX=9606 |KBTBD11 PE=1 SV=1sp|O94819|KBTBB_HUMAN 66 kDa 296 KBTBD11Ezrin OS=Homo sapiens OX=9606 |EZR PE=1 SV=4sp|P15311|EZRI_HUMAN 69 kDa 297 EZRProlow-density lipoprotein receptor-related protein 1OS=Homo sapiens OX=9606 |LRP1 PE=1 SV=2sp|Q07954|LRP1_HUMAN 505 kDa 298 LRP1NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial OS=Homo sapiens OX=9606 sp|Q16795|NDUA9_HUMAN 43 kDa 299 NDUFA9 |NDUFA9 PE=1 SV=2

[0020] Attorney Docket No.07039-2255WO1 2022-307 Isoform 2 of AP-2 complex subunit mu OS=Homo sapiensOX=9606 |AP2M1sp|Q96CW1-2|AP2M1_HUMAN (+1) 49 kDa 300 AP2M1Ubiquitin carboxyl-terminal hydrolase isozyme L1OS=Homo sapiens OX=9606 |UCHL1 PE=1 SV=2sp|P09936|UCHL1_HUMAN 25 kDa 301 UCHL1Isoform Er15 of Ankyrin-1 OS=Homo sapiens OX=9606|ANK1sp|P16157-16|ANK1_HUMAN 204 kDa 302 ANK1Glutathione S-transferase LANCL1 OS=Homo sapiensOX=9606 |LANCL1 PE=1 SV=1sp|O43813|LANC1_HUMAN 45 kDa 303 LANCL1Cell cycle control protein 50A OS=Homo sapiens OX=9606|TMEM30A PE=1 SV=1sp|Q9NV96|CC50A_HUMAN 41 kDa 304 TMEM30AIsoform 4 of Clusterin OS=Homo sapiens OX=9606 |CLUsp|P10909-4|CLUS_HUMAN 49 kDa 305 CLUIsoform 2 of Integrin alpha-V OS=Homo sapiens OX=9606|ITGAVsp|P06756-2|ITAV_HUMAN (+2) 112 kDa 306 ITGAVPolyubiquitin-B OS=Homo sapiens OX=9606 |UBB PE=1SV=1sp|P0CG47|UBB_HUMAN (+3) 26 kDa 307 UBBCDGSH iron-sulfur domain-containing protein 1 OS=Homosapiens OX=9606 |CISD1 PE=1 SV=1sp|Q9NZ45|CISD1_HUMAN 12 kDa 308 CISD1Gap junction alpha-1 protein OS=Homo sapiens OX=9606|GJA1 PE=1 SV=2sp|P17302|CXA1_HUMAN 43 kDa 309 GJA1Isoform 2 of Ganglioside-induced differentiation-associatedprotein 1 OS=Homo sapiens OX=9606 |GDAP1sp|Q8TB36-2|GDAP1_HUMAN (+1) 33 kDa 310 GDAP1Vacuolar protein sorting-associated protein 35 OS=Homosapiens OX=9606 |VPS35 PE=1 SV=2sp|Q96QK1|VPS35_HUMAN 92 kDa 311 VPS35Neurocan core protein OS=Homo sapiens OX=9606 |NCANPE=1 SV=3sp|O14594|NCAN_HUMAN 143 kDa 312 NCANBand 4.1-like protein 1 OS=Homo sapiens OX=9606|EPB41L1 PE=1 SV=2sp|Q9H4G0|E41L1_HUMAN 99 kDa 313 EPB41L1Calmodulin-3 OS=Homo sapiens OX=9606 |CALM3 PE=1SV=1sp|P0DP25|CALM3_HUMAN 17 kDa 314 CALM3Isoform 4 of Clathrin coat assembly protein AP180OS=Homo sapiens OX=9606 |SNAP91sp|O60641-4|AP180_HUMAN (+1) 90 kDa 315 SNAP91Neurofilament light polypeptide OS=Homo sapiensOX=9606 |NEFL PE=1 SV=3sp|P07196|NFL_HUMAN 62 kDa 316 NEFL

[0021] Attorney Docket No.07039-2255WO1 2022-307 NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 OS=Homo sapiens OX=9606 |NDUFB9 PE=1 sp|Q9Y6M9|NDUB9_HUMAN 22 kDa 317 NDUFB9 SV=3 Ras-related protein Rab-18 OS=Homo sapiens OX=9606|RAB18 PE=1 SV=1sp|Q9NP72|RAB18_HUMAN 23 kDa 318 RAB18Sodium / potassium-transporting ATPase subunit beta-3OS=Homo sapiens OX=9606 |ATP1B3 PE=1 SV=1sp|P54709|AT1B3_HUMAN 32 kDa 319 ATP1B3Cytochrome b-c1 complex subunit 7 OS=Homo sapiensOX=9606 |UQCRB PE=1 SV=2sp|P14927|QCR7_HUMAN 14 kDa 320 UQCRBLimbic system-associated membrane protein OS=Homosapiens OX=9606 |LSAMP PE=1 SV=2sp|Q13449|LSAMP_HUMAN 37 kDa 321 LSAMPNADH-cytochrome b5 reductase 1 OS=Homo sapiensOX=9606 |CYB5R1 PE=1 SV=1sp|Q9UHQ9|NB5R1_HUMAN 34 kDa 322 CYB5R1Isoform 2 of CD166 antigen OS=Homo sapiens OX=9606|ALCAMsp|Q13740-2|CD166_HUMAN (+1) 64 kDa 323 ALCAMSolute carrier family 2, facilitated glucose transporter member 3 OS=Homo sapiens OX=9606 |SLC2A3 PE=1 sp|P11169|GTR3_HUMAN 54 kDa 324 SLC2A3 SV=1 ATP synthase F(0) complex subunit B1, mitochondrialOS=Homo sapiens OX=9606 |ATP5PB PE=1 SV=2sp|P24539|AT5F1_HUMAN 29 kDa 325 ATP5PBIsoform 2 of Receptor-type tyrosine-protein phosphatase zetaOS=Homo sapiens OX=9606 |PTPRZ1sp|P23471-2|PTPRZ_HUMAN (+1) 254 kDa 326 PTPRZ160 kDa heat shock protein, mitochondrial OS=Homo sapiensOX=9606 |HSPD1 PE=1 SV=2sp|P10809|CH60_HUMAN 61 kDa 327 HSPD1Isoform 3 of Guanine deaminase OS=Homo sapiensOX=9606 |GDAsp|Q9Y2T3-3|GUAD_HUMAN (+1) 53 kDa 328 GDAFerritin light chain OS=Homo sapiens OX=9606 |FTL PE=1SV=2sp|P02792|FRIL_HUMAN 20 kDa 329 FTLLysosome-associated membrane glycoprotein 1 OS=Homosapiens OX=9606 |LAMP1 PE=1 SV=3sp|P11279|LAMP1_HUMAN 45 kDa 330 LAMP1Isoform 4 of Dynamin-like 120 kDa protein, mitochondrialOS=Homo sapiens OX=9606 |OPA1sp|O60313-10|OPA1_HUMAN (+5) 118 kDa 331 OPA1

[0022] Attorney Docket No.07039-2255WO1 2022-307 Isoform 6 of Dynamin-1-like protein OS=Homo sapiensOX=9606 |DNM1Lsp|O00429-6|DNM1L_HUMAN (+1) 83 kDa 332 DNM1LIsoform 2 of CaM kinase-like vesicle-associated protein sp|Q8NCB2-2|CAMKV_HUMAN OS=Homo sapiens OX=9606 |CAMKV(+1)51 kDa 333 CAMKVFascin OS=Homo sapiens OX=9606 |FSCN1 PE=1 SV=3sp|Q16658|FSCN1_HUMAN 55 kDa 334 FSCN1Isoform 2 of Puromycin-sensitive aminopeptidase OS=Homosapiens OX=9606 |NPEPPSsp|P55786-2|PSA_HUMAN 95 kDa 335 NPEPPSAspartate aminotransferase, mitochondrial OS=Homosapiens OX=9606 |GOT2 PE=1 SV=3sp|P00505|AATM_HUMAN 48 kDa 336 GOT2Solute carrier family 2, facilitated glucose transporter member 1 OS=Homo sapiens OX=9606 |SLC2A1 PE=1 sp|P11166|GTR1_HUMAN 54 kDa 337 SLC2A1 SV=2 Ras-related protein Rab-7a OS=Homo sapiens OX=9606|RAB7A PE=1 SV=1sp|P51149|RAB7A_HUMAN 23 kDa 338 RAB7AIsoform 3 of Septin-2 OS=Homo sapiens OX=9606 |SEPT2sp|Q15019-3|SEPT2_HUMAN 43 kDa 339 4.48E+04Carbonic anhydrase 4 OS=Homo sapiens OX=9606 |CA4PE=1 SV=2sp|P22748|CAH4_HUMAN 35 kDa 340 CA4Isoform 2 of Neutral cholesterol ester hydrolase 1 OS=Homosapiens OX=9606 |NCEH1sp|Q6PIU2-2|NCEH1_HUMAN (+1) 47 kDa 341 NCEH15'-nucleotidase OS=Homo sapiens OX=9606 |NT5E PE=1SV=1sp|P21589|5NTD_HUMAN 63 kDa 342 NT5EAlpha-soluble NSF attachment protein OS=Homo sapiensOX=9606 |NAPA PE=1 SV=3sp|P54920|SNAA_HUMAN 33 kDa 343 NAPADihydropteridine reductase OS=Homo sapiens OX=9606|QDPR PE=1 SV=2sp|P09417|DHPR_HUMAN 26 kDa 344 QDPRNADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 OS=Homo sapiens OX=9606 |NDUFB10 PE=1 sp|O96000|NDUBA_HUMAN 21 kDa 345 NDUFB10 SV=3 Isoform 2 of Long-chain-fatty-acid--CoA ligase 6 OS=Homosapiens OX=9606 |ACSL6sp|Q9UKU0-2|ACSL6_HUMAN (+2) 74 kDa 346 ACSL6Myosin regulatory light chain 12B OS=Homo sapiensOX=9606 |MYL12B PE=1 SV=2sp|O14950|ML12B_HUMAN (+1) 20 kDa 347 MYL12B

[0023] Attorney Docket No.07039-2255WO1 2022-307 NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial OS=Homo sapiens OX=9606 |NDUFS3 PE=1 sp|O75489|NDUS3_HUMAN 30 kDa 348 NDUFS3 SV=1 NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial OS=Homo sapiens OX=9606 sp|O95299|NDUAA_HUMAN 41 kDa 349 NDUFA10 |NDUFA10 PE=1 SV=1 Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial sp|P36957|ODO2_HUMAN 49 kDa 350 DLST OS=Homo sapiens OX=9606 |DLST PE=1 SV=4 HLA class I histocompatibility antigen, A-33 alpha chainOS=Homo sapiens OX=9606 |HLA-A PE=1 SV=3sp|P16190|1A33_HUMAN 41 kDa 351 HLA-AIsoform 2 of Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial OS=Homo sapiens sp|P31040-2|SDHA_HUMAN (+1) 67 kDa 352 SDHA OX=9606 |SDHA T-complex protein 1 subunit theta OS=Homo sapiensOX=9606 |CCT8 PE=1 SV=4sp|P50990|TCPQ_HUMAN 60 kDa 353 CCT8Isoform 2 of Nck-associated protein 1 OS=Homo sapiensOX=9606 |NCKAP1sp|Q9Y2A7-2|NCKP1_HUMAN (+1) 130 kDa 354 NCKAP1Isoform 3 of Gelsolin OS=Homo sapiens OX=9606 |GSNsp|P06396-3|GELS_HUMAN (+2) 82 kDa 355 GSNGlutathione S-transferase P OS=Homo sapiens OX=9606|GSTP1 PE=1 SV=2sp|P09211|GSTP1_HUMAN 23 kDa 356 GSTP1Isoform 3 of Nucleoside diphosphate kinase B OS=Homosapiens OX=9606 |NME2sp|P22392-2|NDKB_HUMAN 30 kDa 357 NME2Peroxisomal multifunctional enzyme type 2 OS=Homosapiens OX=9606 |HSD17B4 PE=1 SV=3sp|P51659|DHB4_HUMAN 80 kDa 358 HSD17B4Synaptojanin-1 OS=Homo sapiens OX=9606 |SYNJ1 PE=1SV=2sp|O43426|SYNJ1_HUMAN 173 kDa 359 SYNJ1Isoform 2 of Cytosolic 10-formyltetrahydrofolatedehydrogenase OS=Homo sapiens OX=9606 |ALDH1L1sp|O75891-2|AL1L1_HUMAN (+1) 88 kDa 360 ALDH1L1Isoform 2 of CD59 glycoprotein OS=Homo sapiensOX=9606 |CD59sp|P13987-2|CD59_HUMAN (+1) 15 kDa 361 CD59Isoform 1 of Serum paraoxonase / arylesterase 2 OS=Homosapiens OX=9606 |PON2sp|Q15165-1|PON2_HUMAN (+1) 39 kDa 362 PON2

[0024] Attorney Docket No.07039-2255WO1 2022-307 Isoform 2 of Membrane-associated progesterone receptorcomponent 2 OS=Homo sapiens OX=9606 |PGRMC2sp|O15173-2|PGRC2_HUMAN (+1) 26 kDa 363 PGRMC2ATP synthase subunit d, mitochondrial OS=Homo sapiensOX=9606 |ATP5PD PE=1 SV=3sp|O75947|ATP5H_HUMAN 18 kDa 364 ATP5PDCytochrome c oxidase subunit 5B, mitochondrial OS=Homosapiens OX=9606 |COX5B PE=1 SV=2sp|P10606|COX5B_HUMAN 14 kDa 365 COX5BReticulon-1 OS=Homo sapiens OX=9606 |RTN1 PE=1SV=1sp|Q16799|RTN1_HUMAN 84 kDa 366 RTN1Isoform Cytoplasmic of Phospholipid hydroperoxideglutathione peroxidase OS=Homo sapiens OX=9606 |GPX4sp|P36969-2|GPX4_HUMAN (+1) 20 kDa 367 GPX4Ras-related protein Rab-11B OS=Homo sapiens OX=9606|RAB11B PE=1 SV=4sp|Q15907|RB11B_HUMAN 24 kDa 368 RAB11BElongation factor 1-gamma OS=Homo sapiens OX=9606|EEF1G PE=1 SV=3sp|P26641|EF1G_HUMAN 50 kDa 369 EEF1GGlutamine synthetase OS=Homo sapiens OX=9606 |GLULPE=1 SV=4sp|P15104|GLNA_HUMAN 42 kDa 370 GLULRho GTPase-activating protein 1 OS=Homo sapiensOX=9606 |ARHGAP1 PE=1 SV=1sp|Q07960|RHG01_HUMAN 50 kDa 371 ARHGAP1T-complex protein 1 subunit gamma OS=Homo sapiensOX=9606 |CCT3 PE=1 SV=4sp|P49368|TCPG_HUMAN 61 kDa 372 CCT3Cytochrome b-c1 complex subunit 9 OS=Homo sapiensOX=9606 |UQCR10 PE=1 SV=3sp|Q9UDW1|QCR9_HUMAN 7 kDa 373 UQCR10OX-2 membrane glycoprotein OS=Homo sapiens OX=9606|CD200 PE=1 SV=4sp|P41217|OX2G_HUMAN 31 kDa 374 CD20040S ribosomal protein S16 OS=Homo sapiens OX=9606|RPS16 PE=1 SV=2sp|P62249|RS16_HUMAN 16 kDa 375 RPS16Isoform 2 of T-complex protein 1 subunit delta OS=Homosapiens OX=9606 |CCT4sp|P50991-2|TCPD_HUMAN 55 kDa 376 CCT4V-type proton ATPase subunit F OS=Homo sapiensOX=9606 |ATP6V1F PE=1 SV=2sp|Q16864|VATF_HUMAN 13 kDa 377 ATP6V1FATP synthase subunit g, mitochondrial OS=Homo sapiensOX=9606 |ATP5MG PE=1 SV=3sp|O75964|ATP5L_HUMAN 11 kDa 378 ATP5MG

[0025] Attorney Docket No.07039-2255WO1 2022-307 Isoform Short of Splicing factor, proline- and glutamine-richOS=Homo sapiens OX=9606 |SFPQsp|P23246-2|SFPQ_HUMAN (+1) 72 kDa 379 SFPQIntercellular adhesion molecule 5 OS=Homo sapiensOX=9606 |ICAM5 PE=1 SV=3sp|Q9UMF0|ICAM5_HUMAN 97 kDa 380 ICAM5Isoform 2 of Solute carrier family 12 member 5 OS=Homosapiens OX=9606 |SLC12A5sp|Q9H2X9-2|S12A5_HUMAN (+1) 124 kDa 381 SLC12A5Transcriptional activator protein Pur-alpha OS=Homosapiens OX=9606 |PURA PE=1 SV=2sp|Q00577|PURA_HUMAN 35 kDa 382 PURAIsoform 2 of Eukaryotic initiation factor 4A-II OS=Homosapiens OX=9606 |EIF4A2sp|Q14240-2|IF4A2_HUMAN (+1) 46 kDa 383 EIF4A2Isoform 2 of DnaJ homolog subfamily C member 5OS=Homo sapiens OX=9606 |DNAJC5sp|Q9H3Z4-2|DNJC5_HUMAN (+1) 19 kDa 384 DNAJC5Isoform 2 of Alpha-actinin-1 OS=Homo sapiens OX=9606|ACTN1sp|P12814-2|ACTN1_HUMAN (+3) 103 kDa 385 ACTN1Cathepsin D OS=Homo sapiens OX=9606 |CTSD PE=1SV=1sp|P07339|CATD_HUMAN 45 kDa 386 CTSDIsoform 2 of Sorcin OS=Homo sapiens OX=9606 |SRIsp|P30626-2|SORCN_HUMAN (+2) 20 kDa 387 SRIHypoxanthine-guanine phosphoribosyltransferase OS=Homosapiens OX=9606 |HPRT1 PE=1 SV=2sp|P00492|HPRT_HUMAN 25 kDa 388 HPRT1Protein kinase C and casein kinase substrate in neurons protein 1 OS=Homo sapiens OX=9606 |PACSIN1 PE=1 sp|Q9BY11|PACN1_HUMAN 51 kDa 389 PACSIN1 SV=1 Isoform 1 of Cell division control protein 42 homologOS=Homo sapiens OX=9606 |CDC42sp|P60953-1|CDC42_HUMAN 21 kDa 390 CDC42Microtubule-associated protein RP / EB family member 2OS=Homo sapiens OX=9606 |MAPRE2 PE=1 SV=1sp|Q15555|MARE2_HUMAN 37 kDa 391 MAPRE2Plectin OS=Homo sapiens OX=9606 |PLEC PE=1 SV=3sp|Q15149|PLEC_HUMAN 532 kDa 392 PLECIsoform 3 of Mitogen-activated protein kinase 3 OS=Homosapiens OX=9606 |MAPK3sp|P27361-3|MK03_HUMAN (+1) 40 kDa 393 MAPK3Isoform 2 of Extended synaptotagmin-1 OS=Homo sapiensOX=9606 |ESYT1sp|Q9BSJ8-2|ESYT1_HUMAN (+1) 124 kDa 394 ESYT1Sodium-dependent neutral amino acid transporter SLC6A17OS=Homo sapiens OX=9606 |SLC6A17 PE=1 SV=3sp|Q9H1V8|S6A17_HUMAN 81 kDa 395 SLC6A17

[0026] Attorney Docket No.07039-2255WO1 2022-307 Myeloid-associated differentiation marker OS=Homosapiens OX=9606 |MYADM PE=1 SV=2sp|Q96S97|MYADM_HUMAN 35 kDa 396 MYADMIsoform 3 of Synaptotagmin-7 OS=Homo sapiens OX=9606|SYT7sp|O43581-3|SYT7_HUMAN (+1) 76 kDa 397 SYT7Destrin OS=Homo sapiens OX=9606 |DSTN PE=1 SV=3sp|P60981|DEST_HUMAN 19 kDa 398 DSTNNADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial OS=Homo sapiens OX=9606 |NDUFV2 PE=1 sp|P19404|NDUV2_HUMAN 27 kDa 399 NDUFV2 SV=2 Adenylate kinase isoenzyme 1 OS=Homo sapiens OX=9606|AK1 PE=1 SV=3sp|P00568|KAD1_HUMAN 22 kDa 400 AK1Ketimine reductase mu-crystallin OS=Homo sapiensOX=9606 |CRYM PE=1 SV=1sp|Q14894|CRYM_HUMAN 34 kDa 401 CRYMsp|Q8WXF7-2|ATLA1_HUMAN Isoform 2 of Atlastin-1 OS=Homo sapiens OX=9606 |ATL1(+1)63 kDa 402 ATL1Isoform 2 of Dehydrogenase / reductase SDR family member7 OS=Homo sapiens OX=9606 |DHRS7sp|Q9Y394-2|DHRS7_HUMAN (+1) 32 kDa 403 DHRS7Cytosolic non-specific dipeptidase OS=Homo sapiensOX=9606 |CNDP2 PE=1 SV=2sp|Q96KP4|CNDP2_HUMAN 53 kDa 404 CNDP2Protein / nucleic acid deglycase DJ-1 OS=Homo sapiensOX=9606 |PARK7 PE=1 SV=2sp|Q99497|PARK7_HUMAN 20 kDa 405 PARK740S ribosomal protein S2 OS=Homo sapiens OX=9606|RPS2 PE=1 SV=2sp|P15880|RS2_HUMAN 31 kDa 406 RPS2Protein furry homolog OS=Homo sapiens OX=9606 |FRYPE=1 SV=1sp|Q5TBA9|FRY_HUMAN 339 kDa 407 FRYCitrate synthase, mitochondrial OS=Homo sapiens OX=9606|CS PE=1 SV=2sp|O75390|CISY_HUMAN 52 kDa 408 CSCytochrome b5 type B OS=Homo sapiens OX=9606|CYB5B PE=1 SV=2sp|O43169|CYB5B_HUMAN 16 kDa 409 CYB5BIsoform 2 of MICOS complex subunit MIC60 OS=Homosapiens OX=9606 |IMMTsp|Q16891-2|MIC60_HUMAN (+2) 83 kDa 410 IMMTPrenylcysteine oxidase 1 OS=Homo sapiens OX=9606|PCYOX1 PE=1 SV=3sp|Q9UHG3|PCYOX_HUMAN 57 kDa 411 PCYOX1

[0027] Attorney Docket No.07039-2255WO1 2022-307 Elongation factor Tu, mitochondrial OS=Homo sapiensOX=9606 |TUFM PE=1 SV=2sp|P49411|EFTU_HUMAN 50 kDa 412 TUFMUbiquitin thioesterase OTUB1 OS=Homo sapiens OX=9606|OTUB1 PE=1 SV=2sp|Q96FW1|OTUB1_HUMAN 31 kDa 413 OTUB1Disintegrin and metalloproteinase domain-containing protein10 OS=Homo sapiens OX=9606 |ADAM10 PE=1 SV=1sp|O14672|ADA10_HUMAN 84 kDa 414 ADAM10Isoform 3 of Voltage-gated potassium channel subunit beta-2OS=Homo sapiens OX=9606 |KCNAB2sp|Q13303-3|KCAB2_HUMAN 47 kDa 415 KCNAB2Hippocalcin-like protein 1 OS=Homo sapiens OX=9606|HPCAL1 PE=1 SV=3sp|P37235|HPCL1_HUMAN 22 kDa 416 HPCAL1AP-2 complex subunit sigma OS=Homo sapiens OX=9606|AP2S1 PE=1 SV=2sp|P53680|AP2S1_HUMAN 17 kDa 417 AP2S1Macrophage migration inhibitory factor OS=Homo sapiensOX=9606 |MIF PE=1 SV=4sp|P14174|MIF_HUMAN 12 kDa 418 MIFIsoform 2 of Neuronal-specific septin-3 OS=Homo sapiensOX=9606 |SEPT3sp|Q9UH03-2|SEPT3_HUMAN (+1) 40 kDa 419 SEPT310 kDa heat shock protein, mitochondrial OS=Homo sapiensOX=9606 |HSPE1 PE=1 SV=2sp|P61604|CH10_HUMAN 11 kDa 420 HSPE1Isoform 2 of Protein disulfide-isomerase A6 OS=Homosapiens OX=9606 |PDIA6sp|Q15084-2|PDIA6_HUMAN (+4) 54 kDa 421 PDIA6Glutaminase kidney isoform, mitochondrial OS=Homosapiens OX=9606 |GLS PE=1 SV=1sp|O94925|GLSK_HUMAN 73 kDa 422 GLS40S ribosomal protein SA OS=Homo sapiens OX=9606|RPSA PE=1 SV=4sp|P08865|RSSA_HUMAN 33 kDa 423 RPSAIsoform 2 of CB1 cannabinoid receptor-interacting protein 1OS=Homo sapiens OX=9606 |CNRIP1sp|Q96F85-2|CNRP1_HUMAN (+1) 14 kDa 424 CNRIP1Isoform 2 of Isocitrate dehydrogenase [NAD] subunitgamma, mitochondrial OS=Homo sapiens OX=9606 |IDH3Gsp|P51553-2|IDH3G_HUMAN (+1) 41 kDa 425 IDH3GADP-ribosylation factor-like protein 8B OS=Homo sapiensOX=9606 |ARL8B PE=1 SV=1sp|Q9NVJ2|ARL8B_HUMAN 22 kDa 426 ARL8BIsoform 2 of Isocitrate dehydrogenase [NADP],mitochondrial OS=Homo sapiens OX=9606 |IDH2sp|P48735-2|IDHP_HUMAN (+1) 45 kDa 427 IDH2

[0028] Attorney Docket No.07039-2255WO1 2022-307 Phenylalanine--tRNA ligase alpha subunit OS=Homosapiens OX=9606 |FARSA PE=1 SV=3sp|Q9Y285|SYFA_HUMAN 58 kDa 428 FARSAPhosphoserine aminotransferase OS=Homo sapiensOX=9606 |PSAT1 PE=1 SV=2sp|Q9Y617|SERC_HUMAN 40 kDa 429 PSAT1Peptidyl-prolyl cis-trans isomerase B OS=Homo sapiensOX=9606 |PPIB PE=1 SV=2sp|P23284|PPIB_HUMAN 24 kDa 430 PPIBUbiquitin-conjugating enzyme E2 N OS=Homo sapiensOX=9606 |UBE2N PE=1 SV=1sp|P61088|UBE2N_HUMAN 17 kDa 431 UBE2NBrevican core protein OS=Homo sapiens OX=9606 |BCANPE=1 SV=2sp|Q96GW7|PGCB_HUMAN 99 kDa 432 BCANCytochrome c oxidase subunit NDUFA4 OS=Homo sapiensOX=9606 |NDUFA4 PE=1 SV=1sp|O00483|NDUA4_HUMAN 9 kDa 433 NDUFA4Isoform 3 of Reticulon-3 OS=Homo sapiens OX=9606|RTN3sp|O95197-3|RTN3_HUMAN 26 kDa 434 RTN3Urea transporter 1 OS=Homo sapiens OX=9606 |SLC14A1PE=1 SV=2sp|Q13336|UT1_HUMAN 43 kDa 435 SLC14A1Isoform Short of Ubiquitin carboxyl-terminal hydrolase 5OS=Homo sapiens OX=9606 |USP5sp|P45974-2|UBP5_HUMAN (+1) 93 kDa 436 USP5Isoform 3 of Actin-related protein 2 / 3 complex subunit 4OS=Homo sapiens OX=9606 |ARPC4sp|P59998-3|ARPC4_HUMAN (+1) 22 kDa 437 ARPC4WD repeat-containing protein 1 OS=Homo sapiensOX=9606 |WDR1 PE=1 SV=4sp|O75083|WDR1_HUMAN 66 kDa 438 WDR1FXYD domain-containing ion transport regulator 6OS=Homo sapiens OX=9606 |FXYD6 PE=1 SV=1sp|Q9H0Q3|FXYD6_HUMAN 11 kDa 439 FXYD640S ribosomal protein S25 OS=Homo sapiens OX=9606|RPS25 PE=1 SV=1sp|P62851|RS25_HUMAN 14 kDa 440 RPS25Far upstream element-binding protein 2 OS=Homo sapiensOX=9606 |KHSRP PE=1 SV=4sp|Q92945|FUBP2_HUMAN 73 kDa 441 KHSRPPhosphoglucomutase-1 OS=Homo sapiens OX=9606 |PGM1PE=1 SV=3sp|P36871|PGM1_HUMAN 61 kDa 442 PGM1Isoform 3 of Glutathione hydrolase 5 proenzyme OS=Homosapiens OX=9606 |GGT5sp|P36269-3|GGT5_HUMAN (+1) 62 kDa 443 GGT5

[0029] Attorney Docket No.07039-2255WO1 2022-307 Isoform 2 of Calcium-dependent secretion activator 1OS=Homo sapiens OX=9606 |CADPSsp|Q9ULU8-2|CAPS1_HUMAN (+3) 144 kDa 444 CADPSStress-70 protein, mitochondrial OS=Homo sapiensOX=9606 |HSPA9 PE=1 SV=2sp|P38646|GRP75_HUMAN 74 kDa 445 HSPA94-aminobutyrate aminotransferase, mitochondrial OS=Homosapiens OX=9606 |ABAT PE=1 SV=3sp|P80404|GABT_HUMAN 56 kDa 446 ABATPhosphatidylinositol 5-phosphate 4-kinase type-2 betaOS=Homo sapiens OX=9606 |PIP4K2B PE=1 SV=1sp|P78356|PI42B_HUMAN 47 kDa 447 PIP4K2BCytochrome b-c1 complex subunit 8 OS=Homo sapiensOX=9606 |UQCRQ PE=1 SV=4sp|O14949|QCR8_HUMAN 10 kDa 448 UQCRQT-complex protein 1 subunit alpha OS=Homo sapiensOX=9606 |TCP1 PE=1 SV=1sp|P17987|TCPA_HUMAN 60 kDa 449 TCP1Isoform 2 of Dihydrolipoyl dehydrogenase, mitochondrialOS=Homo sapiens OX=9606 |DLDsp|P09622-2|DLDH_HUMAN 44 kDa 450 DLDIsoform 3 of Pyruvate dehydrogenase E1 component subunitbeta, mitochondrial OS=Homo sapiens OX=9606 |PDHBsp|P11177-3|ODPB_HUMAN (+1) 38 kDa 451 PDHBIsoform 2 of Methylmalonate-semialdehyde dehydrogenase [acylating], mitochondrial OS=Homo sapiens OX=9606 sp|Q02252-2|MMSA_HUMAN (+1) 56 kDa 452 ALDH6A1 |ALDH6A1 Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial OS=Homo sp|P10515|ODP2_HUMAN 69 kDa 453 DLAT sapiens OX=9606 |DLAT PE=1 SV=3 Heat shock 70 kDa protein 4 OS=Homo sapiens OX=9606|HSPA4 PE=1 SV=4sp|P34932|HSP74_HUMAN 94 kDa 454 HSPA4Isoform 2 of Sodium channel protein type 2 subunit alphaOS=Homo sapiens OX=9606 |SCN2Asp|Q99250-2|SCN2A_HUMAN (+1) 228 kDa 455 SCN2AIsoform 2 of Neuromodulin OS=Homo sapiens OX=9606|GAP43sp|P17677-2|NEUM_HUMAN (+1) 29 kDa 456 GAP43Coronin-1A OS=Homo sapiens OX=9606 |CORO1A PE=1SV=4sp|P31146|COR1A_HUMAN 51 kDa 457 CORO1ALanC-like protein 2 OS=Homo sapiens OX=9606 |LANCL2PE=1 SV=1sp|Q9NS86|LANC2_HUMAN 51 kDa 458 LANCL2

[0030] Attorney Docket No.07039-2255WO1 2022-307 Isoform 3 of Peroxiredoxin-5, mitochondrial OS=Homosapiens OX=9606 |PRDX5sp|P30044-3|PRDX5_HUMAN (+1) 17 kDa 459 PRDX5N(G),N(G)-dimethylarginine dimethylaminohydrolase 1OS=Homo sapiens OX=9606 |DDAH1 PE=1 SV=3sp|O94760|DDAH1_HUMAN 31 kDa 460 DDAH1Histone H4 OS=Homo sapiens OX=9606 |HIST1H4A PE=1SV=2sp|P62805|H4_HUMAN 11 kDa 461 HIST1H4ADynein light chain 2, cytoplasmic OS=Homo sapiensOX=9606 |DYNLL2 PE=1 SV=1sp|Q96FJ2|DYL2_HUMAN 10 kDa 462 DYNLL2Hyaluronan and proteoglycan link protein 3 OS=Homosapiens OX=9606 |HAPLN3 PE=2 SV=1sp|Q96S86|HPLN3_HUMAN 41 kDa 463 HAPLN3Protein NipSnap homolog 1 OS=Homo sapiens OX=9606|NIPSNAP1 PE=1 SV=1sp|Q9BPW8|NIPS1_HUMAN 33 kDa 464 NIPSNAP1Platelet-activating factor acetylhydrolase IB subunit gammaOS=Homo sapiens OX=9606 |PAFAH1B3 PE=1 SV=1sp|Q15102|PA1B3_HUMAN 26 kDa 465 PAFAH1B3Rho GDP-dissociation inhibitor 1 OS=Homo sapiensOX=9606 |ARHGDIA PE=1 SV=3sp|P52565|GDIR1_HUMAN 23 kDa 466 ARHGDIA40S ribosomal protein S13 OS=Homo sapiens OX=9606|RPS13 PE=1 SV=2sp|P62277|RS13_HUMAN 17 kDa 467 RPS13Isoform 2 of Protein RUFY3 OS=Homo sapiens OX=9606|RUFY3sp|Q7L099-2|RUFY3_HUMAN 56 kDa 468 RUFY3Isoform 2 of 4-trimethylaminobutyraldehyde dehydrogenaseOS=Homo sapiens OX=9606 |ALDH9A1sp|P49189-2|AL9A1_HUMAN 46 kDa 469 ALDH9A1Isoform 2 of Protein NDRG2 OS=Homo sapiens OX=9606|NDRG2sp|Q9UN36-2|NDRG2_HUMAN (+2) 39 kDa 470 NDRG2Isoform 2 of Neurotrimin OS=Homo sapiens OX=9606|NTMsp|Q9P121-2|NTRI_HUMAN (+1) 38 kDa 471 NTMActin-related protein 2 / 3 complex subunit 1A OS=Homosapiens OX=9606 |ARPC1A PE=2 SV=2sp|Q92747|ARC1A_HUMAN 42 kDa 472 ARPC1AEH domain-containing protein 2 OS=Homo sapiensOX=9606 |EHD2 PE=1 SV=2sp|Q9NZN4|EHD2_HUMAN 61 kDa 473 EHD2Isoform 2 of Thioredoxin-dependent peroxide reductase,mitochondrial OS=Homo sapiens OX=9606 |PRDX3sp|P30048-2|PRDX3_HUMAN (+1) 26 kDa 474 PRDX3

[0031] Attorney Docket No.07039-2255WO1 2022-307 Isoform 2 of Secernin-1 OS=Homo sapiens OX=9606|SCRN1sp|Q12765-2|SCRN1_HUMAN (+1) 49 kDa 475 SCRN1Isoform 2 of Succinate--CoA ligase [ADP-forming] subunitbeta, mitochondrial OS=Homo sapiens OX=9606 |SUCLA2sp|Q9P2R7-2|SUCB1_HUMAN (+1) 48 kDa 476 SUCLA2Isoform 2 of Lactoylglutathione lyase OS=Homo sapiensOX=9606 |GLO1sp|Q04760-2|LGUL_HUMAN (+1) 19 kDa 477 GLO1Cyclin-dependent-like kinase 5 OS=Homo sapiens OX=9606|CDK5 PE=1 SV=3sp|Q00535|CDK5_HUMAN 33 kDa 478 CDK5Isoform 2 of Neutral alpha-glucosidase AB OS=Homosapiens OX=9606 |GANABsp|Q14697-2|GANAB_HUMAN (+1) 109 kDa 479 GANABWolframin OS=Homo sapiens OX=9606 |WFS1 PE=1 SV=2sp|O76024|WFS1_HUMAN 100 kDa 480 WFS1Isoform 2 of UTP--glucose-1-phosphate uridylyltransferaseOS=Homo sapiens OX=9606 |UGP2sp|Q16851-2|UGPA_HUMAN (+1) 56 kDa 481 UGP2Isoform 2 of Succinate-semialdehyde dehydrogenase,mitochondrial OS=Homo sapiens OX=9606 |ALDH5A1sp|P51649-2|SSDH_HUMAN (+1) 59 kDa 482 ALDH5A1Transmembrane protein 205 OS=Homo sapiens OX=9606|TMEM205 PE=1 SV=1sp|Q6UW68|TM205_HUMAN 21 kDa 483 TMEM205Isoform 2 of Catenin alpha-1 OS=Homo sapiens OX=9606|CTNNA1sp|P35221-2|CTNA1_HUMAN (+1) 103 kDa 484 CTNNA1Hsc70-interacting protein OS=Homo sapiens OX=9606|ST13 PE=1 SV=2sp|P50502|F10A1_HUMAN 41 kDa 485 ST13Multidrug resistance protein 1 OS=Homo sapiens OX=9606|ABCB1 PE=1 SV=3sp|P08183|MDR1_HUMAN 141 kDa 486 ABCB1Cytochrome c OS=Homo sapiens OX=9606 |CYCS PE=1SV=2sp|P99999|CYC_HUMAN 12 kDa 487 CYCSIsoform 2 of Alpha-aminoadipic semialdehydedehydrogenase OS=Homo sapiens OX=9606 |ALDH7A1sp|P49419-2|AL7A1_HUMAN 55 kDa 488 ALDH7A1T-complex protein 1 subunit zeta OS=Homo sapiensOX=9606 |CCT6A PE=1 SV=3sp|P40227|TCPZ_HUMAN 58 kDa 489 CCT6ACatenin beta-1 OS=Homo sapiens OX=9606 |CTNNB1PE=1 SV=1sp|P35222|CTNB1_HUMAN 85 kDa 490 CTNNB1Isoform 2 of Stathmin OS=Homo sapiens OX=9606 |STMN1sp|P16949-2|STMN1_HUMAN (+1) 20 kDa 491 STMN1

[0032] Attorney Docket No.07039-2255WO1 2022-307 F-box only protein 2 OS=Homo sapiens OX=9606 |FBXO2PE=1 SV=2sp|Q9UK22|FBX2_HUMAN 33 kDa 492 FBXO2Proteasome subunit alpha type-4 OS=Homo sapiensOX=9606 |PSMA4 PE=1 SV=1sp|P25789|PSA4_HUMAN 29 kDa 493 PSMA4Isoform 2 of Septin-9 OS=Homo sapiens OX=9606 |SEPT9sp|Q9UHD8-2|SEPT9_HUMAN (+6) 64 kDa 494 SEPT9ProSAAS OS=Homo sapiens OX=9606 |PCSK1N PE=1SV=1sp|Q9UHG2|PCSK1_HUMAN 27 kDa 495 PCSK1NMammalian ependymin-related protein 1 OS=Homo sapiensOX=9606 |EPDR1 PE=1 SV=2sp|Q9UM22|EPDR1_HUMAN 25 kDa 496 EPDR1T-complex protein 1 subunit beta OS=Homo sapiensOX=9606 |CCT2 PE=1 SV=4sp|P78371|TCPB_HUMAN 57 kDa 497 CCT2Cullin-associated NEDD8-dissociated protein 2 OS=Homosapiens OX=9606 |CAND2 PE=1 SV=3sp|O75155|CAND2_HUMAN 135 kDa 498 CAND2Desmoglein-1 OS=Homo sapiens OX=9606 |DSG1 PE=1SV=2sp|Q02413|DSG1_HUMAN 114 kDa 499 DSG1Tetraspanin-7 OS=Homo sapiens OX=9606 |TSPAN7 PE=1SV=2sp|P41732|TSN7_HUMAN 28 kDa 500 TSPAN7Membrane primary amine oxidase OS=Homo sapiensOX=9606 |AOC3 PE=1 SV=3sp|Q16853|AOC3_HUMAN 85 kDa 501 AOC3Contactin-2 OS=Homo sapiens OX=9606 |CNTN2 PE=1SV=1sp|Q02246|CNTN2_HUMAN 113 kDa 502 CNTN2Transaldolase OS=Homo sapiens OX=9606 |TALDO1 PE=1SV=2sp|P37837|TALDO_HUMAN 38 kDa 503 TALDO1Glutathione hydrolase 7 OS=Homo sapiens OX=9606|GGT7 PE=1 SV=2sp|Q9UJ14|GGT7_HUMAN 70 kDa 504 GGT7Profilin-1 OS=Homo sapiens OX=9606 |PFN1 PE=1 SV=2sp|P07737|PROF1_HUMAN (+1) 15 kDa 505 PFN1Acetyl-CoA acetyltransferase, mitochondrial OS=Homosapiens OX=9606 |ACAT1 PE=1 SV=1sp|P24752|THIL_HUMAN 45 kDa 506 ACAT1D-beta-hydroxybutyrate dehydrogenase, mitochondrialOS=Homo sapiens OX=9606 |BDH1 PE=1 SV=3sp|Q02338|BDH_HUMAN 38 kDa 507 BDH1Toll-interacting protein OS=Homo sapiens OX=9606|TOLLIP PE=1 SV=1sp|Q9H0E2|TOLIP_HUMAN 30 kDa 508 TOLLIP

[0033] Attorney Docket No.07039-2255WO1 2022-307 Isoform 2 of Glutathione S-transferase Mu 2 OS=Homosapiens OX=9606 |GSTM2sp|P28161-2|GSTM2_HUMAN (+1) 23 kDa 509 GSTM2Platelet-activating factor acetylhydrolase IB subunit alphaOS=Homo sapiens OX=9606 |PAFAH1B1 PE=1 SV=2sp|P43034|LIS1_HUMAN 47 kDa 510 PAFAH1B1(+1) 38 kDa 511 HP(+1) 72 kDa 512 AMPHFatty 15 kDa 513 FABP5Phosphatidylinositol transfer protein alpha isoformOS=Homo sapiens OX=9606 |PITPNA PE=1 SV=2sp|Q00169|PIPNA_HUMAN 32 kDa 514 PITPNA

[0034] Attorney Docket No.07039-2255WO1 2022-307 TABLE 1B iBAQ value of cell type-specific EV proteins by label-free quantitative mass spectrometry 09 08 08 08 08 08 08 08 08 08 08 08 08 06 07 07 07 08 07 07 07 06 07 00 06 07 06 07 06 05 04 06 06 Attorney Docket No.07039-2255WO1 2022-307 NSF 1.00E+00 1.00E+00 8.07E+05 1.34E+06 1.76E+06 5.06E+06 5.77E+06 3.92E+06 SNAP25 1.00E+00 1.00E+00 2.08E+06 3.86E+06 3.59E+06 1.32E+08 1.29E+08 6.52E+07 SLC1A3 1.00E+00 1.00E+00 4.52E+06 7.36E+06 1.47E+07 4.38E+08 3.70E+08 3.63E+08 SLC3A2 1.00E+00 1.00E+00 1.36E+06 1.91E+06 1.44E+06 3.42E+07 3.77E+07 1.97E+07 GNB1 1.00E+00 1.00E+00 1.56E+07 1.60E+07 2.51E+07 1.72E+08 1.28E+08 7.67E+07 PLP1 1.00E+00 1.00E+00 4.49E+07 4.94E+07 5.01E+07 5.91E+08 5.77E+08 3.63E+08 GNAI1 1.00E+00 1.00E+00 1.04E+07 1.50E+07 1.55E+07 1.08E+08 1.21E+08 8.01E+07 ATP5F1A 1.00E+00 1.00E+00 8.11E+05 1.70E+06 3.17E+06 9.88E+06 1.72E+07 7.83E+06 SYT1 1.00E+00 1.00E+00 2.68E+06 4.61E+06 4.98E+06 1.87E+07 3.15E+07 1.08E+07 PKM 1.00E+00 1.00E+00 2.84E+06 5.64E+06 4.61E+06 1.00E+00 1.00E+00 1.00E+00 PKM 1.00E+00 1.00E+00 2.79E+06 5.52E+06 4.63E+06 5.14E+05 6.48E+05 3.88E+05 CNTNAP1 1.00E+00 1.00E+00 1.39E+05 1.92E+05 1.67E+05 5.67E+06 3.79E+06 1.87E+06 ATP2B3 1.00E+00 1.00E+00 6.41E+05 9.43E+05 1.07E+06 1.04E+07 1.98E+07 7.40E+06 GFAP 1.00E+00 1.00E+00 6.55E+05 1.08E+06 1.07E+06 6.49E+06 6.07E+06 4.14E+06 DPP6 1.00E+00 1.00E+00 3.22E+05 5.73E+05 7.21E+05 7.09E+06 6.22E+06 5.72E+06 SPTAN1 1.00E+00 1.00E+00 3.72E+04 1.56E+05 1.44E+05 1.14E+05 1.37E+05 1.00E+00 SPTBN1 1.00E+00 1.00E+00 8.79E+04 2.37E+05 2.66E+05 3.79E+04 3.11E+05 4.11E+04 EPHX1 1.00E+00 1.00E+00 5.15E+05 1.82E+06 1.57E+06 4.86E+06 7.10E+06 5.57E+06 SLC25A6 1.00E+00 1.00E+00 1.69E+06 4.01E+06 3.48E+06 1.46E+07 1.98E+07 1.19E+07 CANX 1.00E+00 1.00E+00 4.63E+05 9.79E+05 1.33E+06 1.08E+07 1.24E+07 1.18E+07 NCAM1 1.00E+00 1.00E+00 1.42E+06 3.34E+06 4.05E+06 3.14E+07 9.38E+06 1.37E+07 ATP1B2 1.00E+00 1.00E+00 3.20E+06 4.38E+06 3.31E+06 7.55E+07 1.13E+08 1.30E+08 ANXA2 1.00E+00 1.00E+00 2.01E+06 4.35E+06 2.47E+06 1.53E+06 1.95E+06 4.74E+05 MAOB 1.00E+00 1.00E+00 2.25E+05 1.25E+06 1.42E+06 7.90E+06 7.75E+06 6.01E+06 SLC25A12 1.00E+00 1.00E+00 1.93E+05 3.87E+05 3.98E+05 5.15E+06 4.58E+06 2.43E+06 ANXA5 1.00E+00 1.00E+00 1.55E+06 3.11E+06 3.80E+06 1.96E+06 3.61E+06 4.86E+05 ATP8A1 1.00E+00 1.00E+00 6.45E+04 2.33E+05 2.58E+05 1.66E+06 4.28E+06 1.47E+06 SLC25A5 1.00E+00 1.00E+00 2.02E+06 4.57E+06 3.94E+06 1.52E+07 1.66E+07 1.29E+07 STX1B 1.00E+00 1.00E+00 1.50E+06 3.24E+06 3.10E+06 5.22E+07 5.25E+07 1.52E+07 VDAC1 1.00E+00 1.00E+00 2.32E+06 3.00E+06 4.33E+06 3.11E+07 4.61E+07 7.01E+06 SLC25A4 1.00E+00 1.00E+00 1.16E+06 3.91E+06 3.59E+06 1.12E+07 2.07E+07 1.19E+07 GNB2 1.00E+00 1.00E+00 7.43E+06 9.31E+06 1.39E+07 5.56E+07 5.81E+07 4.10E+07 FLOT2 1.00E+00 1.00E+00 2.19E+05 3.29E+05 3.45E+05 2.13E+06 8.11E+06 1.60E+06 FLOT1 1.00E+00 1.00E+00 1.66E+05 4.82E+05 5.18E+05 5.39E+06 9.40E+06 4.40E+06 HSP90AA1 1.00E+00 1.00E+00 9.75E+05 1.57E+06 1.51E+06 3.38E+06 3.93E+06 2.66E+05 NFASC 1.00E+00 1.00E+00 3.21E+05 4.72E+05 7.04E+05 9.12E+06 3.31E+06 2.17E+06 HSP90AB1 1.00E+00 1.00E+00 9.48E+05 1.76E+06 1.62E+06 3.74E+06 4.88E+06 1.00E+00 CAMK2A 1.00E+00 1.00E+00 2.91E+06 5.99E+06 6.18E+06 5.82E+06 5.62E+06 1.88E+06 ATP2A2 1.00E+00 1.00E+00 1.21E+05 3.15E+05 3.26E+05 3.84E+06 4.14E+06 5.53E+05 Attorney Docket No.07039-2255WO1 2022-307 GNAS 1.00E+00 1.00E+00 3.84E+06 5.66E+06 5.89E+06 3.88E+07 4.26E+07 3.02E+07 HSPA8 1.00E+00 1.00E+00 8.94E+05 1.45E+06 1.65E+06 1.64E+06 8.81E+05 1.00E+00 1.00E+00 1.00E+00 7.24E+06 8.01E+06 1.10E+07 1.85E+08 2.08E+08 1.48E+08 1.00E+00 1.00E+00 1.25E+06 2.50E+06 3.22E+06 3.98E+07 6.38E+07 2.75E+07 1.00E+00 1.00E+00 3.73E+05 8.79E+05 6.91E+05 2.89E+06 4.91E+06 4.68E+06 1.00E+00 1.00E+00 9.15E+06 7.23E+06 1.23E+07 1.78E+08 1.38E+08 5.73E+07 1.00E+00 1.00E+00 3.59E+05 6.60E+05 6.08E+05 1.33E+07 1.29E+07 1.21E+07 1.00E+00 1.00E+00 1.97E+07 2.79E+07 3.85E+07 2.16E+07 1.55E+07 1.20E+07 1.00E+00 1.00E+00 1.11E+06 2.51E+06 3.24E+06 7.55E+06 1.03E+07 7.95E+06 1.00E+00 1.00E+00 7.42E+06 8.11E+06 8.32E+06 1.17E+07 3.00E+07 4.38E+07 1.00E+00 1.00E+00 3.38E+06 1.30E+07 9.08E+06 1.34E+08 1.88E+08 1.64E+08 1.00E+00 1.00E+00 5.86E+04 1.39E+05 2.83E+05 1.17E+06 1.85E+06 2.10E+06 1.00E+00 1.00E+00 1.57E+06 2.82E+06 2.63E+06 1.01E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.28E+05 7.19E+05 6.37E+05 5.66E+06 8.66E+06 1.37E+06 1.00E+00 1.00E+00 1.02E+06 1.48E+06 1.03E+06 2.85E+07 3.96E+07 2.59E+07 1.00E+00 1.00E+00 7.13E+05 1.79E+06 1.45E+06 1.20E+07 1.47E+07 9.05E+06 1.00E+00 1.00E+00 1.06E+06 2.95E+06 1.23E+06 1.75E+06 1.27E+06 1.00E+00 1.00E+00 1.00E+00 1.50E+05 5.96E+05 6.06E+05 7.65E+05 4.61E+06 2.86E+06 1.00E+00 1.00E+00 1.06E+07 1.19E+07 1.58E+07 6.25E+07 8.79E+07 4.92E+07 1.00E+00 1.00E+00 9.54E+05 2.31E+06 2.41E+06 5.86E+06 6.42E+06 4.72E+06 1.00E+00 1.00E+00 2.14E+04 6.10E+04 8.96E+04 3.36E+06 5.61E+06 1.82E+06 1.00E+00 1.00E+00 2.01E+06 1.92E+06 2.37E+06 2.84E+06 8.09E+06 1.99E+06 1.00E+00 1.00E+00 1.10E+06 1.38E+06 1.44E+06 2.67E+06 6.63E+05 1.48E+06 1.00E+00 1.00E+00 1.05E+05 4.14E+05 5.87E+05 3.02E+05 9.54E+05 2.55E+05 1.00E+00 1.00E+00 6.29E+05 1.04E+06 1.76E+06 1.84E+07 2.21E+07 7.15E+05 1.00E+00 1.00E+00 1.73E+06 2.49E+06 2.65E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.99E+06 7.30E+06 7.82E+06 5.41E+07 5.66E+07 4.17E+07 1.00E+00 1.00E+00 5.44E+05 1.00E+06 9.02E+05 1.00E+00 1.44E+05 1.00E+00 1.00E+00 1.00E+00 2.16E+06 4.31E+06 3.94E+06 1.34E+07 1.47E+07 1.02E+07 1.00E+00 1.00E+00 1.30E+07 3.20E+07 3.09E+07 3.87E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 9.17E+05 2.33E+06 2.47E+06 2.93E+07 2.51E+07 9.76E+06 1.00E+00 1.00E+00 2.05E+06 2.14E+06 4.40E+06 1.00E+00 1.02E+07 6.02E+06 1.00E+00 1.00E+00 9.98E+04 4.63E+05 4.39E+05 1.51E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.11E+05 1.56E+06 1.13E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.84E+05 3.74E+05 1.61E+05 1.22E+07 1.49E+07 7.21E+06 1.00E+00 1.00E+00 1.90E+05 5.24E+05 8.82E+05 3.33E+06 4.62E+06 1.00E+00 1.00E+00 1.00E+00 1.18E+06 2.63E+06 1.92E+06 3.91E+06 9.22E+06 9.36E+05 1.00E+00 1.00E+00 2.04E+05 2.38E+05 2.55E+05 9.33E+05 1.19E+06 1.00E+06 1.00E+00 1.00E+00 5.01E+04 9.23E+04 1.31E+05 1.56E+06 1.68E+06 1.64E+06 Attorney Docket No.07039-2255WO1 2022-307 NNT 1.00E+00 1.00E+00 3.71E+04 2.10E+05 1.88E+05 1.94E+06 1.80E+06 1.67E+06 SLC1A4 1.00E+00 1.00E+00 2.35E+05 4.82E+05 7.58E+05 2.32E+07 2.32E+07 2.16E+07 1.00E+00 1.00E+00 2.03E+06 3.96E+06 2.95E+06 3.53E+07 6.06E+06 1.00E+00 1.00E+00 1.00E+00 7.40E+05 1.11E+06 1.00E+06 5.54E+06 4.62E+06 1.00E+00 1.00E+00 1.00E+00 3.33E+05 3.56E+05 4.22E+05 1.17E+06 5.40E+05 1.00E+00 1.00E+00 1.00E+00 6.26E+05 1.02E+06 1.09E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.29E+06 4.09E+06 4.12E+06 3.80E+07 2.82E+07 1.71E+07 1.00E+00 1.00E+00 1.81E+06 2.21E+06 1.81E+06 1.42E+07 1.31E+07 4.51E+06 1.00E+00 1.00E+00 9.86E+05 1.12E+06 2.27E+06 4.70E+06 1.11E+07 4.08E+06 1.00E+00 1.00E+00 2.61E+06 3.17E+06 3.67E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.21E+05 9.32E+05 1.63E+06 3.77E+06 9.27E+06 5.36E+06 1.00E+00 1.00E+00 1.02E+06 2.70E+06 2.93E+06 1.00E+00 3.25E+05 1.00E+00 1.00E+00 1.00E+00 1.19E+06 1.69E+06 1.07E+06 1.73E+07 1.42E+07 1.11E+07 1.00E+00 1.00E+00 4.99E+05 2.15E+06 2.22E+06 3.46E+06 6.73E+06 4.47E+06 1.00E+00 1.00E+00 1.84E+05 6.11E+05 7.53E+05 5.65E+06 7.09E+06 7.94E+06 1.00E+00 1.00E+00 6.63E+05 1.70E+06 1.24E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 8.44E+04 4.56E+05 5.71E+05 2.60E+06 2.55E+06 1.00E+00 1.00E+00 1.00E+00 3.45E+04 1.41E+05 2.29E+05 3.13E+05 3.31E+05 4.06E+05 1.00E+00 1.00E+00 1.17E+04 6.94E+04 6.53E+04 1.17E+05 1.17E+05 1.00E+00 1.00E+00 1.00E+00 1.27E+06 2.76E+06 3.20E+06 3.61E+05 3.31E+05 1.00E+00 1.00E+00 1.00E+00 4.61E+05 1.04E+06 1.06E+06 3.05E+06 7.38E+06 5.03E+06 1.00E+00 1.00E+00 2.79E+04 3.27E+05 5.68E+05 9.10E+06 1.29E+07 5.97E+06 1.00E+00 1.00E+00 2.12E+04 9.35E+03 3.87E+03 1.63E+05 4.96E+05 1.64E+06 1.00E+00 1.00E+00 3.11E+05 6.94E+05 9.38E+05 1.00E+00 2.14E+06 9.94E+04 1.00E+00 1.00E+00 5.32E+04 1.90E+05 2.79E+05 4.13E+05 4.03E+05 1.00E+00 1.00E+00 1.00E+00 1.45E+05 2.56E+05 4.32E+05 5.80E+05 7.01E+05 1.00E+00 1.00E+00 1.00E+00 2.25E+05 4.26E+05 3.29E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.07E+05 7.14E+05 1.20E+06 6.12E+07 5.17E+07 1.00E+00 1.00E+00 1.00E+00 2.06E+05 4.78E+05 3.91E+05 1.23E+06 1.04E+06 4.61E+05 1.00E+00 1.00E+00 1.04E+05 2.37E+05 1.84E+05 7.56E+05 1.05E+06 1.00E+00 1.00E+00 1.00E+00 8.83E+05 1.04E+06 1.50E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.55E+05 4.41E+05 6.65E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 8.24E+05 8.63E+05 1.06E+06 7.53E+06 1.95E+07 1.69E+07 1.00E+00 1.00E+00 1.60E+06 3.55E+06 4.72E+06 2.61E+07 4.57E+07 8.48E+06 1.00E+00 1.00E+00 3.86E+05 4.36E+05 3.79E+05 1.18E+06 2.70E+06 1.22E+06 1.00E+00 1.00E+00 5.04E+05 4.78E+05 4.04E+05 2.17E+06 3.25E+06 5.76E+05 1.00E+00 1.00E+00 6.09E+05 1.29E+06 7.89E+05 2.37E+06 4.71E+06 1.33E+06 1.00E+00 1.00E+00 4.98E+04 8.02E+04 1.19E+05 7.79E+06 6.53E+06 3.95E+06 1.00E+00 1.00E+00 1.58E+05 3.73E+05 3.27E+05 1.00E+00 4.92E+05 1.00E+00 Attorney Docket No.07039-2255WO1 2022-307 PRDX2 1.00E+00 1.00E+00 1.33E+06 3.13E+06 2.30E+06 6.52E+06 8.95E+06 1.00E+00 RAB14 1.00E+00 1.00E+00 7.28E+05 1.48E+06 1.66E+06 1.00E+00 4.76E+06 1.00E+00 1.00E+00 1.00E+00 1.85E+05 3.78E+05 5.44E+05 5.38E+06 8.16E+06 3.46E+06 1.00E+00 1.00E+00 4.76E+04 1.30E+05 9.75E+04 2.52E+06 4.79E+06 1.95E+06 1.00E+00 1.00E+00 1.56E+05 5.86E+05 6.05E+05 9.78E+06 2.20E+07 6.99E+06 1.00E+00 1.00E+00 1.49E+05 4.04E+05 4.84E+05 3.66E+06 2.03E+06 7.63E+05 1.00E+00 1.00E+00 5.93E+05 9.29E+05 9.07E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.01E+06 3.33E+06 3.66E+06 2.20E+07 4.02E+07 8.36E+06 1.00E+00 1.00E+00 2.19E+05 5.07E+05 7.05E+05 3.66E+06 2.51E+06 1.43E+06 1.00E+00 1.00E+00 1.08E+05 2.54E+05 2.42E+05 2.55E+05 1.00E+00 1.73E+05 1.00E+00 1.00E+00 3.10E+05 4.02E+05 2.98E+05 2.06E+06 2.36E+06 1.23E+06 1.00E+00 1.00E+00 2.16E+05 4.55E+05 9.16E+05 1.09E+07 1.03E+07 5.24E+06 1.00E+00 1.00E+00 2.47E+04 5.44E+04 2.24E+04 3.72E+05 1.47E+06 1.00E+00 1.00E+00 1.00E+00 9.80E+04 1.49E+05 1.21E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.86E+06 5.00E+06 2.14E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.24E+06 1.16E+06 1.63E+06 1.00E+00 2.76E+06 1.20E+06 1.00E+00 1.00E+00 2.34E+06 1.98E+06 4.14E+06 2.97E+06 1.02E+07 1.00E+00 1.00E+00 1.00E+00 9.92E+05 1.50E+06 1.58E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.06E+05 1.20E+05 2.99E+05 2.55E+06 3.64E+06 3.16E+06 1.00E+00 1.00E+00 2.19E+04 1.13E+05 1.29E+05 1.32E+06 2.31E+06 2.18E+06 1.00E+00 1.00E+00 4.29E+06 6.76E+06 6.31E+06 1.19E+07 1.57E+07 1.05E+07 1.00E+00 1.00E+00 3.30E+04 1.90E+05 3.01E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.23E+06 2.56E+06 3.03E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.54E+04 7.06E+04 9.24E+04 3.00E+05 6.70E+05 2.40E+05 1.00E+00 1.00E+00 5.24E+03 6.23E+04 8.32E+04 1.00E+00 1.01E+05 1.00E+00 1.00E+00 1.00E+00 2.54E+06 1.82E+06 4.90E+06 1.00E+00 1.25E+07 1.00E+00 1.00E+00 1.00E+00 3.75E+05 9.55E+05 6.04E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.92E+04 2.88E+05 3.21E+05 3.72E+06 1.45E+06 2.85E+06 1.00E+00 1.00E+00 3.19E+04 1.43E+05 1.19E+05 1.13E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.58E+04 7.61E+04 1.01E+05 3.96E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.96E+05 9.16E+05 1.07E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.54E+05 5.82E+05 6.36E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.10E+04 3.24E+05 3.28E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.71E+05 1.12E+06 1.23E+06 1.00E+00 4.20E+06 1.00E+00 1.00E+00 1.00E+00 4.07E+05 6.94E+05 5.75E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.64E+05 2.63E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.46E+05 5.57E+05 6.34E+05 7.50E+06 8.91E+06 1.10E+07 1.00E+00 1.00E+00 1.58E+05 1.83E+05 2.07E+05 7.10E+05 3.70E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.16E+04 6.06E+04 1.09E+06 9.00E+05 8.77E+05 Attorney Docket No.07039-2255WO1 2022-307 HAPLN2 1.00E+00 1.00E+00 6.17E+05 4.74E+05 4.51E+05 6.26E+05 1.00E+00 1.00E+00 VCP 1.00E+00 1.00E+00 2.82E+04 1.74E+05 1.28E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 8.25E+05 1.57E+06 1.54E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.75E+04 6.52E+04 9.79E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.11E+05 4.67E+05 8.03E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.12E+05 5.90E+05 2.28E+06 3.20E+06 9.42E+05 1.00E+00 1.00E+00 1.00E+00 1.25E+05 2.45E+05 1.00E+00 3.43E+05 1.22E+06 1.00E+00 1.00E+00 8.31E+05 1.30E+06 1.79E+06 1.82E+07 2.44E+05 3.12E+06 1.00E+00 1.00E+00 8.84E+04 9.82E+04 1.05E+05 3.06E+05 1.37E+05 1.00E+00 1.00E+00 1.00E+00 9.95E+04 3.52E+05 3.29E+05 1.72E+06 2.02E+06 5.78E+05 1.00E+00 1.00E+00 2.39E+05 6.67E+05 8.12E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.87E+06 3.79E+06 3.55E+06 1.04E+08 9.64E+07 9.84E+07 1.00E+00 1.00E+00 2.78E+05 3.53E+05 1.79E+05 7.06E+06 9.18E+06 4.49E+06 1.00E+00 1.00E+00 3.40E+05 3.01E+05 4.09E+05 9.83E+05 9.68E+05 6.36E+05 1.00E+00 1.00E+00 3.88E+04 6.10E+05 5.09E+05 3.02E+05 8.15E+05 4.20E+05 1.00E+00 1.00E+00 1.00E+00 2.83E+04 2.11E+05 1.20E+06 2.42E+06 5.22E+05 1.00E+00 1.00E+00 1.83E+05 5.38E+05 7.98E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.47E+06 2.25E+06 2.77E+06 1.92E+07 5.82E+07 4.42E+07 1.00E+00 1.00E+00 2.51E+04 4.52E+04 5.49E+04 3.85E+05 1.25E+05 1.00E+00 1.00E+00 1.00E+00 2.11E+05 3.99E+05 3.42E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.44E+05 3.39E+05 3.74E+05 1.00E+00 5.92E+05 1.00E+00 1.00E+00 1.00E+00 3.31E+04 2.68E+05 1.77E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.81E+06 1.98E+06 2.39E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.65E+05 1.34E+05 9.55E+05 1.60E+07 1.63E+07 6.25E+06 1.00E+00 1.00E+00 1.09E+05 2.56E+05 1.24E+05 2.56E+06 9.59E+06 1.88E+06 1.00E+00 1.00E+00 6.47E+04 1.97E+05 2.60E+05 3.80E+06 4.61E+06 2.73E+06 1.00E+00 1.00E+00 6.41E+04 1.41E+05 1.52E+05 1.00E+00 1.46E+06 1.00E+00 1.00E+00 1.00E+00 3.46E+05 4.38E+05 5.61E+05 1.32E+07 1.20E+07 1.00E+00 1.00E+00 1.00E+00 4.39E+05 8.38E+05 4.99E+05 3.66E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.64E+05 1.02E+06 1.11E+06 5.54E+05 4.14E+05 1.00E+00 1.00E+00 1.00E+00 3.87E+04 2.31E+05 2.20E+05 6.27E+05 3.09E+05 1.00E+00 1.00E+00 1.00E+00 2.25E+04 6.53E+04 7.13E+04 5.49E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.20E+05 6.94E+05 3.12E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.27E+05 1.43E+06 1.13E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.51E+05 1.99E+05 3.22E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.76E+05 8.63E+05 7.09E+05 1.63E+07 9.26E+06 6.49E+06 1.00E+00 1.00E+00 4.87E+04 3.31E+04 2.39E+04 1.36E+06 9.61E+05 6.83E+05 1.00E+00 1.00E+00 1.00E+00 2.60E+04 2.06E+04 6.48E+05 8.31E+05 1.00E+00 1.00E+00 1.00E+00 4.80E+04 2.06E+05 4.46E+05 1.00E+00 3.06E+06 2.71E+06 Attorney Docket No.07039-2255WO1 2022-307 SCARB2 1.00E+00 1.00E+00 1.61E+05 4.64E+05 2.80E+05 3.12E+05 1.17E+06 8.86E+05 GNAZ 1.00E+00 1.00E+00 6.71E+04 2.70E+05 1.94E+05 7.73E+05 4.46E+05 4.47E+05 1.00E+00 4.40E+05 7.76E+05 6.26E+05 8.35E+05 5.05E+05 1.00E+00 1.00E+00 1.19E+06 3.02E+06 1.94E+06 3.33E+06 1.00E+00 1.00E+00 1.00E+00 9.84E+04 4.21E+05 5.16E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.39E+06 3.49E+06 3.90E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.38E+04 1.45E+05 1.67E+05 2.37E+06 5.64E+06 1.00E+00 1.00E+00 1.08E+05 2.18E+05 3.89E+05 3.59E+05 2.26E+05 1.00E+00 1.00E+00 3.59E+04 8.21E+04 2.15E+05 3.67E+05 2.52E+05 9.36E+04 1.00E+00 1.20E+06 1.98E+06 2.76E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.19E+05 3.83E+05 1.60E+05 1.33E+07 1.12E+06 6.81E+06 1.00E+00 5.69E+04 3.05E+05 2.60E+05 3.77E+06 4.26E+05 1.00E+00 1.00E+00 3.96E+04 1.22E+05 1.60E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.79E+05 3.89E+05 3.51E+05 1.71E+06 1.00E+00 6.17E+05 1.00E+00 1.66E+05 4.38E+05 3.99E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.83E+04 1.00E+00 1.38E+06 2.20E+06 1.81E+06 1.00E+00 1.31E+05 8.24E+05 2.62E+05 5.12E+06 1.67E+07 7.71E+06 1.00E+00 3.65E+04 4.01E+05 3.07E+05 3.48E+06 4.10E+06 3.10E+06 1.00E+00 8.56E+04 1.20E+05 1.74E+05 1.00E+00 4.27E+05 3.53E+05 1.00E+00 1.00E+00 2.12E+05 1.44E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.85E+04 2.15E+05 7.83E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.97E+04 2.00E+05 2.07E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.67E+04 2.02E+04 1.35E+05 1.00E+00 1.00E+00 1.00E+00 1.26E+05 3.39E+05 1.84E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.48E+04 3.30E+05 3.06E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.68E+05 3.57E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.11E+05 1.59E+05 1.65E+05 2.20E+06 2.40E+06 1.00E+00 1.00E+00 4.13E+05 8.74E+05 6.30E+05 4.31E+06 4.01E+06 3.63E+06 1.00E+00 1.39E+04 1.25E+05 5.64E+04 8.98E+05 2.01E+06 6.86E+05 1.00E+00 2.86E+05 2.31E+05 2.70E+05 2.98E+07 2.09E+07 8.54E+06 1.00E+00 3.25E+05 9.28E+04 4.90E+05 9.59E+05 1.00E+00 1.00E+00 1.00E+00 6.82E+04 2.16E+05 2.32E+05 1.42E+06 1.32E+06 1.00E+00 1.00E+00 1.00E+00 6.28E+04 5.73E+04 2.05E+05 1.96E+05 1.15E+05 1.00E+00 4.84E+04 1.57E+05 1.08E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.56E+06 8.11E+05 3.45E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.68E+05 3.31E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.24E+04 4.93E+04 8.14E+04 9.27E+05 1.09E+06 6.34E+05 1.00E+00 8.56E+04 1.23E+05 9.66E+04 3.18E+06 2.04E+06 1.84E+06 1.00E+00 3.69E+05 6.47E+05 2.73E+05 4.08E+06 5.09E+06 9.03E+06 Attorney Docket No.07039-2255WO1 2022-307 SLC25A22 1.00E+00 1.00E+00 7.41E+04 2.39E+05 3.29E+05 1.32E+06 1.30E+06 1.61E+06 MT-CO2 1.00E+00 1.00E+00 1.30E+06 2.22E+06 2.81E+06 1.00E+00 4.20E+07 5.43E+06 Attorney Docket No.07039-2255WO1 2022-307 NCAN 1.00E+00 1.00E+00 4.94E+04 3.03E+04 5.72E+04 1.00E+00 2.11E+05 1.00E+00 EPB41L1 1.00E+00 1.00E+00 6.06E+04 9.36E+04 9.99E+04 3.81E+05 1.00E+00 1.00E+00 Attorney Docket No.07039-2255WO1 2022-307 HLA-A 1.00E+00 1.00E+00 5.88E+04 2.16E+05 1.18E+05 5.67E+05 1.00E+00 1.00E+00 SDHA 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.22E+05 6.76E+05 1.00E+00 Attorney Docket No.07039-2255WO1 2022-307 CDC42 1.00E+00 1.00E+00 1.00E+00 3.11E+05 1.63E+05 1.00E+00 1.00E+00 1.00E+00 MAPRE2 1.00E+00 1.00E+00 5.76E+04 2.85E+05 8.98E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.79E+03 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.10E+05 1.42E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.31E+03 1.76E+05 9.17E+04 9.13E+04 1.00E+00 1.00E+00 1.00E+00 9.08E+03 6.72E+04 6.18E+05 4.07E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.51E+05 2.99E+05 1.00E+00 2.83E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.14E+04 1.00E+00 3.40E+05 3.51E+05 2.37E+05 1.00E+00 1.00E+00 3.50E+04 1.00E+00 2.59E+05 1.00E+00 4.99E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.27E+05 1.00E+00 1.00E+00 1.44E+06 1.00E+00 1.00E+00 1.00E+00 4.42E+04 2.01E+05 1.83E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.14E+04 2.62E+05 4.02E+05 7.16E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.46E+04 7.66E+04 6.83E+04 1.00E+00 4.71E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.85E+04 7.00E+04 1.00E+00 8.57E+05 1.00E+00 1.00E+00 1.00E+00 3.08E+04 9.14E+04 4.19E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.40E+05 1.87E+05 2.76E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.99E+04 7.79E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.51E+03 1.00E+00 6.62E+03 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.60E+04 2.80E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.26E+05 6.71E+05 7.63E+06 1.00E+00 8.11E+06 1.00E+00 1.00E+00 1.28E+04 1.81E+04 3.78E+04 1.77E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.04E+04 2.40E+04 2.15E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.25E+05 8.98E+04 4.57E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.72E+04 5.92E+04 1.42E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.03E+04 1.17E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.29E+04 9.16E+04 1.00E+00 4.56E+05 1.00E+00 1.00E+00 1.00E+00 8.86E+04 1.93E+05 2.55E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.26E+05 5.83E+05 4.53E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.34E+05 7.98E+05 9.59E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.95E+04 1.87E+05 1.32E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.37E+05 1.90E+05 3.53E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.62E+04 7.33E+04 1.62E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.23E+04 4.87E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.99E+04 6.90E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.37E+05 3.12E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.45E+04 1.00E+00 8.37E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.21E+04 4.17E+04 1.41E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 9.33E+04 6.27E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.70E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 Attorney Docket No.07039-2255WO1 2022-307 PSAT1 1.00E+00 1.00E+00 1.00E+00 6.99E+04 4.26E+04 1.00E+00 1.00E+00 1.00E+00 PPIB 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.81E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.90E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.05E+04 9.58E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.01E+05 5.42E+05 1.00E+00 2.09E+06 1.00E+00 1.00E+00 1.00E+00 4.65E+05 9.16E+05 6.42E+05 5.16E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.39E+05 3.09E+05 2.71E+05 1.00E+00 6.19E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.46E+04 1.37E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.98E+04 1.29E+05 1.41E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.22E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.00E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.38E+05 4.69E+05 2.56E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.51E+06 6.93E+05 2.84E+05 1.00E+00 1.00E+00 1.00E+00 1.03E+04 2.09E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.18E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.35E+04 6.52E+03 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1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.47E+05 2.93E+05 2.79E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.18E+05 1.59E+05 4.63E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.46E+05 1.70E+05 1.55E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.57E+05 2.05E+05 2.79E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.29E+04 4.14E+04 1.07E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.59E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.45E+04 1.75E+04 3.79E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 9.91E+04 2.66E+05 1.84E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.64E+04 1.54E+05 1.50E+05 1.00E+00 1.00E+00 1.00E+00 Attorney Docket No.07039-2255WO1 2022-307 RUFY3 1.00E+00 1.00E+00 1.00E+00 1.78E+04 2.34E+04 1.00E+00 1.00E+00 1.00E+00 ALDH9A1 1.00E+00 1.00E+00 1.00E+00 4.89E+04 9.88E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+05 7.73E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.23E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.06E+04 2.10E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.87E+04 2.28E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.62E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.15E+04 5.79E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.37E+04 4.24E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.00E+04 5.88E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.29E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.63E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.85E+04 2.92E+04 1.00E+00 3.65E+05 1.00E+00 1.00E+00 1.00E+00 2.10E+04 4.06E+04 2.52E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.71E+04 3.23E+04 5.76E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.62E+05 2.54E+05 3.70E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.12E+04 2.38E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 6.14E+04 4.66E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 9.25E+03 2.07E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.04E+05 1.00E+00 3.45E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.90E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.65E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.37E+04 1.70E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.66E+05 2.51E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.29E+05 6.42E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.16E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.71E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.20E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.93E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.04E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 3.63E+04 1.05E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 8.51E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.63E+05 1.04E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.35E+04 3.84E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.74E+05 1.06E+05 1.00E+00 1.00E+00 1.00E+00 1.00E+00 7.03E+04 5.33E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.53E+04 1.92E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.45E+05 1.54E+06 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.30E+04 1.00E+00 1.00E+00 1.00E+00 Attorney Docket No.07039-2255WO1 2022-307 BDH1 1.00E+00 1.00E+00 1.00E+00 1.79E+04 1.70E+04 1.00E+00 1.00E+00 1.00E+00 TOLLIP 1.00E+00 1.00E+00 1.00E+00 3.66E+04 1.00E+00 1.00E+00 1.00E+00 1.00E+00 00 00 00 00 00 00 9 8 8 8 8 8 8 8 8 8 8 8 8 6 7 7 7 8 7 6 7 6 7 6 6 6 Attorney Docket No.07039-2255WO1 2022-307 CNP 1.62E+06 4.21E+06 6.60E+06 4.05E+07 2.92E+07 3.84E+07 GNAI2 3.60E+07 3.28E+07 3.57E+07 6.69E+07 8.70E+07 8.31E+07

[0035] Attorney Docket No.07039-2255WO1 2022-307 FLOT2 1.00E+00 2.74E+05 4.53E+05 3.45E+05 1.03E+06 1.56E+06 FLOT1 1.00E+00 1.00E+00 2.23E+05 1.31E+06 2.13E+06 3.68E+06

[0036] Attorney Docket No.07039-2255WO1 2022-307 DNM3 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 GDI1 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00

[0037] Attorney Docket No.07039-2255WO1 2022-307 SLC17A7 3.73E+06 1.00E+00 1.00E+00 5.01E+06 1.82E+07 2.35E+07 CD9 1.00E+00 3.83E+06 1.00E+00 2.32E+07 5.31E+07 2.68E+07

[0038] Attorney Docket No.07039-2255WO1 2022-307 NCDN 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 RAB6A 1.00E+00 1.00E+00 1.00E+00 1.00E+00 4.16E+06 1.00E+00

[0039] Attorney Docket No.07039-2255WO1 2022-307 GSTM3 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 PGAM1 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00

[0040] Attorney Docket No.07039-2255WO1 2022-307 GPD2 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 2.17E+05 EHD3 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 5.04E+05

[0041] Attorney Docket No.07039-2255WO1 2022-307 CLU 1.00E+00 1.00E+00 1.00E+00 4.70E+05 4.18E+05 1.00E+00 ITGAV 1.00E+00 1.00E+00 1.00E+00 1.94E+05 1.16E+05 2.57E+05

[0042] Attorney Docket No.07039-2255WO1 2022-307 QDPR 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 NDUFB10 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.99E+06 2.16E+06

[0043] Attorney Docket No.07039-2255WO1 2022-307 EIF4A2 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 DNAJC5 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00

[0044] Attorney Docket No.07039-2255WO1 2022-307 GLS 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 RPSA 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00

[0045] Attorney Docket No.07039-2255WO1 2022-307 HIST1H4A 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 DYNLL2 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00

[0046] Attorney Docket No.07039-2255WO1 2022-307 TSPAN7 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 AOC3 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 0 0 0 0 0 0 0 0 0 0 0 0 0

[0047] Attorney Docket No.07039-2255WO1 2022-307 TABLE 2: Assessment of AD-related pathogenic proteins in CSF samples by Simoa assays Protein concentration (pg ml–1) 1 Control 2 Control 3 AD 1 AD 2 AD 3CSF A?40Too high 2338.86 Too high 1076.71 465.67 1144.77CSF A?42Too high 192.14 Too high 72.31 39.77 98.92CSF T-tauToo high 2193.38 Too high 2309.28 1612.55 13032.74CSF P-tau1811734.93 135.38 593.44 132.72 90.52 339.15CSF SNAP251160.63 253.02 1662.95 414.47 300.55 954.69CSF-EV A?4031.45 114.80 163.48 45.68 19.40 53.90CSF-EV A?4213.48 14.61 22.14 7.29 3.22 8.51CSF-EV T-tau1415.98 384.47 2807.61 237.18 242.22 542.64CSF-EV P-tau18141.60 13.71 59.17 9.63 10.87 18.67CSF-EV SNAP25170.17 Too low 144.52 Too low Too low Too lowATP1A3-IP CSF-EV ??4010.63 14.74 40.75 2.01 4.06 5.58ATP1A3-IP CSF-EV A?426.43 3.03 8.22 1.10 1.13 3.07ATP1A3-IP CSF-EV T-tau238.55 56.44 360.76 28.58 60.86 114.13ATP1A3-IP CSF-EV P-tau1817.06 1.19 5.94 0.61 1.17 1.63ATP1A3-IP CSF-EV SNAP25291.29 Too low 143.82 Too low Too low Too low

[0048] Attorney Docket No.07039-2255WO1 2022-307 TABLE 3: Assessment of AD-related pathogenic proteins in total plasma by Simoa assays Protein conce –ntration (pg ml1) ??40 ??42 T-tau ??42 / 40 ratio Control_1 254.09 10.21 2.59 0.040 Control_2 N / A N / A N / A N / A Control_3 204.91 7.25 2.97 0.035 Control_4 278.57 13.04 2.44 0.047 Control_5 212.63 8.49 5.14 0.040 Control_6 241.20 10.96 4.14 0.045 Control_7 298.09 13.45 2.41 0.045 Control_8 236.14 10.06 11.08 0.043 Control_9 159.98 6.68 4.53 0.042 Control_10 253.09 10.59 5.01 0.042 MCI_1 356.57 14.90 3.93 0.042 MCI_2 259.16 11.20 12.14 0.043 MCI_3 300.06 14.43 5.24 0.048 MCI_4 346.37 12.29 3.37 0.035 MCI_5 207.67 9.32 2.81 0.045 MCI_6 262.33 7.72 2.39 0.029 MCI_7 330.50 12.25 3.10 0.037 MCI_8 249.91 9.88 4.67 0.040 MCI_9 278.65 10.43 4.93 0.037 MCI_10134.40 1.92 3.65 0.014 AD_1 282.40 7.99 4.64 0.028 320.60 10.99 4.77 0.034 307.76 10.75 5.65 0.035 313.19 12.97 3.61 0.041 342.32 11.69 4.53 0.034 240.58 9.46 1.61 0.039 214.57 9.17 2.47 0.043 197.15 7.78 1.88 0.039 260.54 9.79 3.95 0.038 244.20 9.65 4.32 0.040 Attorney Docket No.07039-2255WO1 2022-307 TABLES 4A-4E: Demographic information for human samples TABLE 4A: Brain Tissues for Immuno-EM / ExoView analysis / Super-resolution imaging / Western blot / Mass spectrometry Sample BRAAK PMI Primary IDCase ID AgeStageNeurodegeneration Diffuse Amyloid Gender(hrs) Diagnosis #1 20916 95 Stage II No neuritic plaquesFrequent diffuseplaques None Female 5.25 nonAD#2 10640 69 Stage IModerate neuriticModerate diffuse Moderate Male 12 nonAD plaques plaques #3 20847 91 Stage II No neuritic plaques No diffuse plaques None Male 10.02 nonAD #4 21047 95 Stage IISparse neuriticSparse diffuse plaques plaquesMild Female 12.30 nonAD#5 10611 95 Stage IIISparse neuriticFrequent diffuse Moderate Male 10 nonAD plaques plaques #6 20637 82 Stage II No neuritic plaques No diffuse plaques Mild Female 4 nonAD

[0049] Attorney Docket No.07039-2255WO1 2022-307 TABLE 4B: 1st Cohort CSF samples for Immuno-EM / ExoView analysis / Super-resolution imaging / Western blot / ELISA Case ID Age Gender Diagnosis 13431-0 c 62 M AD 13593-0 c 81 M AD 12848-0 c23 81 M AD 12700-0 c8 79 F AD 12762-0 c24 62 M AD 12250-0 c8 89 F AD 13367-0 c21 87 M AD 12708-0 c5 84 M Myelodysplastic syndrome 13102-0 c39 78 F AD 13339-0 c24 87 F AD 13251-0 c21 86 M AD 13284-0 c5 66 M CA, lung 13100-0 c6 66 F AD 13090 80 M CA, pancreas 13116 63 M CA, colon with metastasis to liver

[0050] Attorney Docket No.07039-2255WO1 2022-307 TABLE 4C: 2nd Cohort CSF samples for Simoa assays nder Age Plaq Case ID GePMIue (hrs)Control AD MCI Total Density Stage 19511 Male 85 3.5 yes no yes 0 zero I 17227 Female 95 3.5 yes no yes 2 sparse III 97-50 Female 88 2.15 yes no yes 0 zero I 31260 Male 82 3.66 yes no yes 0 zero III 12936 Male 89 3.33 yes no no 6.5 moderate III 44727 Female 87 2.5 yes no no 4.5 moderate III 44744 Female 87 3 no yes no 15 frequent V 44627 Male 67 2 no yes no 11 frequent V 44579 Male 86 3 no yes no 14.25 moderate V 44724 Female 74 4 no yes no 15 frequent VI 44757 Male 80 3.16 no yes no 15 frequent VI 12789-0 Unknown Unknown Unknown no yes Unknown Unknown Unknown Unknown TABLE 4D: 1st Cohort plasma samples for Immuno-EM / ExoView analysis / Super-resolution imaging / Western blot / ELISA Case ID Gender Age PMI (hrs) Diagnosis Braak Stage X5709 Male 94 12 Normal II X5687 Male 84 8 Normal, Acute ischemic changes I X5628 Female 80 12 Normal I

[0051] Attorney Docket No.07039-2255WO1 2022-307 TABLE 4E: 2nd Cohort plasma samples for SIMOA / Super-resolution imaging Sample AGE SEXPMI Diagnosis MBraak ID (hrs)MSE DRSStageApoE1 84 M 36 Normal 30 143 2 2 / 3 2 94 M 12 Normal 30 141 2 3 / 3 3 83 F 72 Normal 29 140 1 2 / 4 4 84 M 8 Normal 28 141 1 3 / 3 5 80 F 12 Normal 29 136 1 3 / 3 6 93 F 18 Normal 30 142 1 3 / 3 7 83 M N / A Normal 28 136 1 3 / 3 8 84 F N / A Normal N / A N / A N / A N / A 9 70 M N / A Normal N / A N / A N / A N / A 10 72 F N / A Normal N / A N / A N / A N / A 1 89 M 12 MCI 18 98 3 3 / 4 2 86 M 8 MCI 23 122 4 3 / 3 3 88 M 40 MCI 23 108 4 3 / 3 4 93 F 6 MCI 21 15 2 3 / 3 5 90 F 12 MCI 24 132 3 3 / 4 6 78 M 5 MCI 25 122 2 3 / 3 7 90 F 4 MCI 15 115 3 3 / 3 8 102 F 25 MCI 26 136 3 2 / 4 9 86 M 4 MCI 25 118 2 3 / 4 10 83 F 8 MCI 23 104 4 3 / 4 1 81 M 5 AD 18 104 6 3 / 4 2 85 F 6 AD 7 62 6 4 / 4 3 85 M 39 AD 1 80 6 3 / 4 4 78 F 10 AD 15 76 6 3 / 3 5 85 M N / A AD 3 87 5 3 / 4 6 83 F 5 AD 4 44 6 3 / 4 7 89 F 12 AD 8 3 6 3 / 3 8 73 F 8 AD 0 49 6 4 / 4 9 88 M 6 AD 0 17 6 3 / 3 10 78 M 12 AD 2 5 6 3 / 4

[0052] Attorney Docket No.07039-2255WO1 2022-307 TABLE 5: Antibodies and sources Antibody Source anti-ATP1A3 ThermoFisher Scientific, Cat# MA3915 7 S Attorney Docket No.07039-2255WO1 2022-307 anti-SNAP25 BioLegend, Cat# 836304 anti-TMEM119 Sigma-Aldrich, Cat# HPA051870 Data-independent Acquisition Liquid Chromatography-Mass-Spectrometry and ALAMAR NULISAseq120-plex CNS Disease Panel To determine the applicability of directly immunoprecipitating ATP1A3+EVs from plasma samples, human plasma samples (3 AD and 3 control cases; 500 ?L each) were tested for immunoprecipitation of ATP1A3+by an anti-ATP1A3 antibody, followed by data independent acquisition (DIA)-based liquid chromatography mass-spectrometry (LC-MS) for proteomic profiling. In particular, a biotinylated antibody against ATP1A3 was used to directly immunoprecipitate ATP1A3+EVs from human plasma samples (500 ?L / sample) from three healthy controls and three AD patients. The ATP1A3+EVs were purified by biotin-streptavidin binding and lysed with RIPA buffer. The protein lysates from ATP1A3+EVs were then subjected to label free data independent acquisition (DIA)-based liquid chromatography mass-spectrometry (LC-MS) for proteomic profiling. A total of 1721 plasma proteins were identified (1680 proteins in control (CTL), and 1699 proteins in AD) (FIG.19). The proteins were selected in at least one out of three samples. The proteomics data from direct immunoprecipitation of ATP1A3+components from plasma revealed significant association with extracellular vesicles, with the identification of enriched EV markers including CD9, CD63, FLOT1, and syntenin-1, and a lower abundance of plasma serum proteins such as albumin and IgG. Notably, the immunoprecipitated ATP1A3+particles were enriched with multiple synaptic proteins, including SNP23, ESYT1, SV2A and VAMP2, suggesting the neuronal specificity of the ATP1A3+particles and successful isolation of neuronal EVs from whole plasma using the direct immunoprecipitation methodology. Attorney Docket No.07039-2255WO1 2022-307 The proteins of interest in ATP1A3+EVs that were identified from mass spectrometry as listed in FIG.20. Protein expression (labeled as Log2 protein value) of several disease-associated proteins, neuron-specific proteins, astrocyte-specific proteins, and EV marker proteins in both control and AD groups are shown (FIG.20). The fold changes of proteins in AD versus control also are listed (FIG.20). Many disease-related proteins were identified from the ATP1A3+plasma-EVs, which were more enriched in AD compared to control. Neuron-specific proteins but not astrocyte-specific proteins were found in the ATP1A3+EVs, suggesting the neuron origin of these EV samples. In addition, high expression of EV-related proteins also was found, revealing the successful immunoprecipitation of the EV population using the biotinylated ATP1A3 antibody. NULISA™ Assay The NULISAseq platform (Alamar Biosciences) and the 120-plex CNS disease panel, which includes 120 disease associated proteins (FIG.21), was introduced into the workflow. NUcleic acid Linked Immuno-Sandwich Assay (NULISA), a liquid biopsy platform for high-plex proteomic profiling, leverages oligonucleotide-conjugated antibodies, a dual capture and release mechanism, and proximity ligation to suppress assay background and achieve attomolar detection sensitivity. A schematic of the assay workflow is shown in FIG.22. This experiment was performed to profile neuro and cytokine / inflammatory response proteins in human plasma and plasma-derived EV samples from patients with AD compared to control donors using the NULISAseq platform. A total of 28 human neat plasma samples, 28 total plasma-derived EVs (Total EV), and 28 ATP1A3+plasma- derived EVs (IP EV) were analyzed. ATP1A3+EVs were isolated and lysed using the same method as described above. The protein detectability results are presented in FIG.23. The detectability was the percentage of samples above the limit of detection (LOD). A target was considered detectable if at least 50% of samples were above LOD. Overall, 98.4%, 52.4%, and 44.4% of the targets were detected in neat plasma samples, total EVs and ATP1A3+EVs, respectively (FIG.23). Attorney Docket No.07039-2255WO1 2022-307 The Venn diagram in FIG.24 shows the unique targets detected in total EVs and ATP1A3+EVs. Among them, 12 targets were uniquely detected in ATP1A3+EVs, and 22 targets were uniquely detected in total EVs (FIG.24). The detectability of disease-associated proteins showed a good coverage not only in total EVs, but also in ATP1A3+EVs (FIG.25). More neuron-associated proteins and fewer astrocyte-associated proteins were detectable in ATP1A3+EVs as compared to total EVs, suggesting the neuronal specificity of ATP1A3+EVs. In addition, EV- associated targets were detected in total EVs as well as ATP1A3+EVs, suggesting the good quality of the EV preparations. Protein expression levels (indicated by protein NPQ values) were compared between ATP1A3+EV and total EV (FIG.26A), as well as between ATP1A3+EV and neat plasma (FIG.26B). Proteins that were more enriched in ATP1A3+plasma EVs included disease associated molecules such as pSNCA-129, Oligo-SNCA, pTDP43-409, TARDBP, SNCA, TREM2, APP, SOD1, and HTT. These proteins are related to Lewy body dementia, Frontotemporal lobar degeneration, Parkinson’ s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, and Huntington disease. The results provided herein suggest that ATP1A3+EVs are superior to total EVs and neat plasma for disease biomarker development and detection. The significantly differentiated candidates in ATP1A3+plasma-EVs included ACHE, FABP3, and TREM2. The ACHE, FABP3, and TREM2 proteins were each significantly decreased in ATP1A3+EVs from the AD group as compared to the control group (FIG.27). These results demonstrate that the presence of a reduced protein expression level of ACHE, FABP3, TREM2, or any combination thereof in ATP1A3+plasma-EVs can be used to identify AD patients. Acetylcholine esterase (ACHE) regulates cholinergic synaptic transmission and is the therapeutic target of the first FDA- approved drug of AD (Donepezil). FABP3 (fatty acid binding protein 3) is a carrier of polyunsaturated fatty acids. It is elevated in the cerebrospinal fluid of AD cases, but its plasma levels were not correlated due to its higher expression in peripheral tissues (Sepe et al., Future Neurology, 13(4):199-207 (2018)). TREM2 is an AD risk gene and is specifically expressed in microglia and myeloid cells. Soluble TREM2 is increased in the Attorney Docket No.07039-2255WO1 2022-307 cerebrospinal fluid of AD cases, but its plasma level was not correlated due to its higher expression in peripheral myeloid cells. OTHER EMBODIMENTS It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.07039-2255WO1 2022-307 WHAT IS CLAIMED IS:

1. A method for identifying a mammal as having, or as being likely to have, Alzheimer’s disease (AD), wherein said method comprises: obtaining extracellular vesicles (EVs) derived from a biological sample from said mammal; determining that said EVs comprise ATPase Na+ / K+Transporting Subunit Alpha 3 (ATP1A3); and assessing the level of one or more biomarkers associated with AD in said EVs and ascertaining that said EVs have an elevated level of said one or more biomarkers; thereby identifying said mammal as having, or as being likely to have, AD.

2. The method of claim 1, wherein said mammal is a human.

3. The method of claim 1 or claim 2, wherein said biological sample is a plasma sample.

4. The method of claim 1 or claim 2, wherein said biological sample is a cerebrospinal fluid (CSF) sample.

5. The method of claim 1 or claim 2, wherein said biological sample is a brain tissue sample or a brain lysate.

6. The method of any one of claims 1 to 5, wherein said determining comprises contacting said EVs with an anti-ATP1A3 antibody.

7. The method of claim 6, wherein said anti-ATP1A3 antibody comprises a first label.

8. The method of any one of claims 1 to 7, wherein said assessing comprises contacting said EVs with one or more antibodies against said one or more biomarkers.Attorney Docket No.07039-2255WO1 2022-307 9. The method of claim 8, wherein said one or more antibodies each comprise a label that is different from said first label.

10. The method of any one of claims 1 to 9, wherein said one or more biomarkers comprise one or more of amyloid-? peptide 1-40 (A?40), amyloid-? peptide 1-42 (A?42), total tau, ptau at T181 (P-tau181), and SNAP25.

11. A method for treating a mammal identified as having, or as being likely to have, AD, wherein said method comprises: (a) identifying said mammal as having, or as being likely to have, AD by (i) obtaining EVs derived from a biological sample from said mammal, (ii) determining that said EVs comprise ATP1A3, and (iii) assessing the level of one or more biomarkers associated with AD in said EVs and ascertaining that said EVs have an elevated level of said one or more biomarkers; and (b) administering to said mammal one or more therapeutic agents for treating said AD.

12. The method of claim 11, wherein said mammal is a human.

13. The method of claim 11 or claim 12, wherein said biological sample is a plasma sample.

14. The method of claim 11 or claim 12, wherein said biological sample is a CSF sample.

15. The method of claim 11 or claim 12, wherein said biological sample is a brain tissue sample or a brain lysate.

16. The method of any one of claims 11 to 15, wherein said determining comprises contacting said EVs with an anti-ATP1A3 antibody.

17. The method of claim 16, wherein said anti-ATP1A3 antibody comprises a first label.Attorney Docket No.07039-2255WO1 2022-307 18. The method of any one of claims 11 to 17, wherein said assessing comprises contacting said EVs with one or more antibodies against said one or more biomarkers.

19. The method of claim 18, wherein said one or more antibodies each comprise a label that is different from said first label.

20. The method of any one of claims 11 to 19, wherein said one or more biomarkers comprise one or more of amyloid-? peptide 1-40 (A?40), amyloid-? peptide 1-42 (A?42), total tau, ptau at T181 (P-tau181), and SNAP25.

21. The method of any one of claims 11 to 20, comprising administering a therapeutic agent selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab.

22. The method of claim 21, comprising administering a cholinesterase inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine.

23. The method of any one of claims 11 to 22, further comprising monitoring said mammal for progression of said AD.

24. A method for treating a mammal identified as having, or as being likely to have, AD, wherein said method comprises: administering, to a mammal identified as having plasma- or CSF-derived EVs that (a) comprise ATP1A3 and (b) have an elevated level of one or more biomarkers associated with AD, one or more therapeutic agents for treating said AD.

25. The method of claim 24, wherein said mammal is a human.

26. The method of claims 24 or claim 25, comprising administering a therapeutic agent selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab.Attorney Docket No.07039-2255WO1 2022-307 27. The method of claim 26, comprising administering a cholinesterase inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine.

28. The method of any one of claims 24 to 27, further comprising monitoring said mammal for progression of said AD.

29. A method comprising: providing a solid substrate comprising a surface having discrete areas to which one or more EV capture molecules are attached; contacting said surface with a sample comprising one or more EVs, such that said one or more EVs bind to said one or more EV capture molecules; immunostaining said bound EVs with one or more labeled antibodies, wherein each of said one or more labeled antibodies is targeted to a biomarker for a selected cell type or disorder, and wherein each of said one or more labeled antibodies comprises a detectable label; and imaging said immunostained EVs to detect the presence of each said detectable label.

30. The method of claim 29, wherein said solid substrate comprises a glass slide.

31. The method of claim 29, wherein said solid substrate comprises a glass coverslip.

32. The method of any one of claims 29 to 31, wherein said one or more EV capture molecules comprise a capture antibody.

33. The method of claim 32, wherein said capture antibody is an anti-CD9 antibody, an anti-CD63 antibody, or an anti-CD81 antibody.

34. The method of claim 32, wherein said capture antibody is an anti-ATP1A3 antibody.

35. The method of claim 32, wherein said capture antibody is an antibody against a marker for oligodendrocytes, a marker for astrocytes, or a marker for microglia.Attorney Docket No.07039-2255WO1 2022-307 36. The method of claim 35, wherein said capture antibody is an antibody against a marker for oligodendrocytes, and wherein said marker for oligodendrocytes is LAMP2, FTH1, or PLP1.

37. The method of claim 35, wherein said capture antibody is an antibody against a marker for astrocytes, and wherein said marker for astrocytes is LRP1, ITGA6, or EAAT1.

38. The method of claim 35, wherein said capture antibody is an antibody against a marker for microglia, and wherein said marker for microglia is ITGAM, LCP1, or P2RY12.

39. The method of any one of claims 29 to 38, wherein said one or more labeled antibodies comprise an antibody against a marker for AD.

40. The method of claim 39, wherein said marker for AD is selected from the group consisting of amyloid-? peptide 1-40 (A?40), amyloid-? peptide 1-42 (A?42), total tau, ptau at T181 (P-tau181), and SNAP25.

41. The method of any one of claims 29 to 38, wherein said one or more labeled antibodies comprise an antibody against a marker for Parkinson’s disease, an antibody against a marker for amyotrophic lateral sclerosis (ALS), or an antibody against a marker for frontotemporal dementia (FTD).

42. The method of claim 41, wherein said one or more labeled antibodies comprise an antibody against a marker for Parkinson’s disease, and wherein said marker for Parkinson’s disease is alpha-synuclein.

43. The method of claim 41, wherein said one or more labeled antibodies comprise an antibody against a marker for ALS or FTD, and wherein said marker for ALS or FTD is Tau or TDP-43.Attorney Docket No.07039-2255WO1 2022-307 44. The method of any one of claims 29 to 43, wherein said imaging comprises one or more of high-sensitivity digital ELISA (Simoa), SP-IRIS (ExoView), direct Stochastic Optical Reconstruction Microscopy (dSTORM), single-molecule localization microscopy (SMLM), proximal ligation amplification (PLA), and Nanoflow Cytometry (NanoFCM).

45. A method for identifying a mammal as having, or as being likely to have, AD, wherein said method comprises determining that EVs derived from a biological sample from said mammal and determined to comprise ATP1A3 have an elevated level of one or more biomarkers associated with AD, thereby identifying said mammal as having, or as being likely to have, AD.

46. The method of claim 45, wherein said mammal is a human.

47. The method of claim 45 or claim 46, wherein said biological sample is a plasma sample.

48. The method of claim 45 or claim 46, wherein said biological sample is a CSF sample.

49. The method of claim 45 or claim 46, wherein said biological sample is a brain tissue sample or a brain lysate.

50. The method of any one of claims 45 to 49, wherein said determining comprises contacting said EVs with one or more antibodies against said one or more biomarkers.

51. The method of claim 50, wherein said one or more antibodies each comprise a different label.

52. The method of any one of claims 45 to 51, wherein said biomarkers comprise one or more of amyloid-? peptide 1-40 (A?40), amyloid-? peptide 1-42 (A?42), total tau, ptau at T181 (P-tau181), and SNAP25.Attorney Docket No.07039-2255WO1 2022-307 53. A method for treating a mammal identified as having, or as being likely to have, AD, wherein said method comprises: (a) identifying said mammal as having, or as being likely to have, AD by determining that EVs derived from a biological sample from said mammal and determined to comprise ATP1A3 have an elevated level of one or more biomarkers associated with AD, and (b) administering, to said mammal, one or more therapeutic agents for treating said AD.

54. The method of claim 53, wherein said mammal is a human.

55. The method of claim 53 or claim 54, wherein said biological sample is a plasma sample.

56. The method of claim 53 or claim 54, wherein said biological sample is a CSF sample.

57. The method of claim 53 or claim 54, wherein said biological sample is a brain tissue sample or a brain lysate.

58. The method of any one of claims 53 to 57, wherein said determining comprises contacting said EVs with one or more antibodies against said one or more biomarkers.

59. The method of claim 58, wherein said one or more antibodies each comprise a different label.

60. The method of any one of claims 53 to 59, wherein said biomarkers comprise one or more of amyloid-? peptide 1-40 (A?40), amyloid-? peptide 1-42 (A?42), total tau, ptau at T181 (P-tau181), and SNAP25.

61. The method of any one of claims 53 to 60, comprising administering a therapeutic agent selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab.Attorney Docket No.07039-2255WO1 2022-307 62. The method of claim 61, comprising administering a cholinesterase inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine.

63. The method of any one of claims 53 to 62, further comprising monitoring said mammal for progression of said AD.

64. A method for identifying a mammal as having, or as being likely to have, a neurologic disorder, wherein said method comprises determining that ATPase Na+ / K+Transporting Subunit Alpha 3-positive extracellular vesicles (ATP1A3+EVs) obtained from a biological sample of said mammal comprise (a) the presence of an elevated level of a biomarker elevated in ATP1A3+EVs of said neurologic disorder or (b) the presence of a reduced level of a biomarker reduced in ATP1A3+EVs of said neurologic disorder, thereby identifying said mammal as having, or as being likely to have, said neurologic disorder.

65. The method of claim 64, wherein said mammal is a human.

66. The method of claim 64 or claim 65, wherein said biological sample is a plasma sample.

67. The method of claim 64 or claim 65, wherein said biological sample is a cerebrospinal fluid (CSF) sample.

68. The method of claim 64 or claim 65, wherein said biological sample is a brain tissue sample or a brain lysate.

69. The method of any one of claims 64 to 68, wherein said ATP1A3+EVs were isolated from said biological sample using an anti-ATP1A3 antibody.

70. The method of claim 69, wherein said anti-ATP1A3 antibody comprises a first label.Attorney Docket No.07039-2255WO1 2022-307 71. The method of any one of claims 64 to 70, wherein said method comprises determining that said ATP1A3+EVs comprise said presence of said elevated level of said biomarker elevated in ATP1A3+EVs of said neurologic disorder.

72. The method of claim 71, wherein said presence of said elevated level of said biomarker elevated in ATP1A3+EVs of said neurologic disorder is determined using an antibody against said biomarker elevated in ATP1A3+EVs of said neurologic disorder.

73. The method of claim 72, wherein said antibody against said biomarker elevated in ATP1A3+EVs of said neurologic disorder comprises a label that is different from said first label.

74. The method of any one of claims 64 to 73, wherein said neurologic disorder is Alzheimer’s disease (AD).

75. The method of claim 74, wherein said biomarker elevated in ATP1A3+EVs of said AD is selected from the group consisting of amyloid-? peptide 1-40 (A?40), amyloid-? peptide 1-42 (A?42), total tau, ptau at T181 (P-tau181), T217 (P-tau217), T231 (P-tau231), neurofilament light chain (NEFL), and SNAP25.

76. The method of any one of claims 64 to 73, wherein said neurologic disorder is selected from the group consisting of Parkinson’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, and brain tumors.

77. The method of claim 76, wherein: (a) said neurologic disorder is Parkinson’s disease, and wherein said biomarker elevated in ATP1A3+EVs of said Parkinson’s disease is selected from the group consisting of alpha-synuclein, oligomeric alpha-synuclein, phosphorylated alpha- synuclein, and PARK7,Attorney Docket No.07039-2255WO1 2022-307 (b) said neurologic disorder is ALS, and wherein said biomarker elevated in ATP1A3+EVs of said ALS is selected from the group consisting of Tau, TDP-43, and SOD1, (c) said neurologic disorder is FTD, and wherein said biomarker elevated in ATP1A3+EVs of said FTD is selected from the group consisting of Tau, TDP-43, and phosphorylated TDP-43, (d) said neurologic disorder is multiple sclerosis, and wherein said biomarker elevated in ATP1A3+EVs of said multiple sclerosis is selected from the group consisting of CCL26, CCL22, and CXCL10, (e) said neurologic disorder is chronic traumatic encephalopathy, and wherein said biomarker elevated in ATP1A3+EVs of said chronic traumatic encephalopathy is selected from the group consisting of Tau, phosphorylated tau, and NEFL, (f) said neurologic disorder is Huntington’s disease, and wherein said biomarker elevated in ATP1A3+EVs of said Huntington’s disease is HTT, (g) said neurologic disorder is prion disease, and wherein said biomarker elevated in ATP1A3+EVs of said prion disease is selected from the group consisting of Tau, phosphorylated tau, and NEFL, (h) said neurologic disorder is viral encephalitis, and wherein said biomarker elevated in ATP1A3+EVs of said viral encephalitis is selected from the group consisting of IFNG, IL1B, and TNF, (i) said neurologic disorder is cerebrovascular disease, and wherein said biomarker elevated in ATP1A3+EVs of said cerebrovascular disease is selected from the group consisting of APOE, SAA1, and VCAM1, or (j) said neurologic disorder is a brain tumor, and wherein said biomarker elevated in ATP1A3+EVs of said brain tumor is selected from the group consisting of GFAP, S100B, and VGF.

78. The method of any one of claims 64 to 77, wherein said method comprises determining that said ATP1A3+EVs comprise said presence of said reduced level of said biomarker reduced in ATP1A3+EVs of said neurologic disorder.Attorney Docket No.07039-2255WO1 2022-307 79. The method of claim 78, wherein said presence of said reduced level of said biomarker reduced in ATP1A3+EVs of said neurologic disorder is determined using an antibody against said biomarker reduced in ATP1A3+EVs of said neurologic disorder.

80. The method of claim 79, wherein said antibody against said biomarker reduced in ATP1A3+EVs of said neurologic disorder comprises a label that is different from said first label.

81. The method of any one of claims 78 to 80, wherein said neurologic disorder is Alzheimer’s disease (AD).

82. The method of claim 81, wherein said biomarker reduced in ATP1A3+EVs of said AD is selected from the group consisting of ACHE, FABP3, and TREM2.

83. A method for treating a mammal having, or likely having, a neurologic disorder, wherein said method comprises administering a treatment agent for said neurologic disorder to a mammal identified as having ATPase Na+ / K+Transporting Subunit Alpha 3- positive extracellular vesicles (ATP1A3+EVs) that comprise (a) the presence of an elevated level of a biomarker elevated in ATP1A3+EVs of said neurologic disorder or (b) the presence of a reduced level of a biomarker reduced in ATP1A3+EVs of said neurologic disorder.

84. The method of claim 83, wherein said mammal is a human.

85. The method of claim 83 or claim 84, wherein said ATP1A3+EVs are plasma ATP1A3+EVs.

86. The method of claim 83 or claim 84, wherein said ATP1A3+EVs are cerebrospinal fluid (CSF) ATP1A3+EVs.

87. The method of claim 83 or claim 84, wherein said ATP1A3+EVs are brain tissue ATP1A3+EVs or brain lysate ATP1A3+EVs.Attorney Docket No.07039-2255WO1 2022-307 88. The method of any one of claims 83 to 87, wherein said mammal was identified as having said ATP1A3+EVs that comprise said presence of said elevated level of said biomarker elevated in ATP1A3+EVs of said neurologic disorder.

89. The method of claim 88, wherein said presence of said elevated level of said biomarker elevated in ATP1A3+EVs of said neurologic disorder was determined using an antibody against said biomarker elevated in ATP1A3+EVs of said neurologic disorder.

90. The method of any one of claims 83 to 89, wherein said neurologic disorder is Alzheimer’s disease (AD).

91. The method of claim 90, wherein said biomarker elevated in ATP1A3+EVs of said AD is selected from the group consisting of amyloid-? peptide 1-40 (A?40), amyloid-? peptide 1-42 (A?42), total tau, ptau at T181 (P-tau181), and SNAP25.

92. The method of claim 90 or claim 91, wherein said treatment agent for said AD is selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab.

93. The method of any one of claims 83 to 89, wherein said neurologic disorder is selected from the group consisting of Parkinson’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis, chronic traumatic encephalopathy, Huntington’s disease, prion disease, viral encephalitis, cerebrovascular disease, and brain tumors.

94. The method of claim 93, wherein: (a) said neurologic disorder is Parkinson’s disease, wherein said biomarker elevated in ATP1A3+EVs of said Parkinson’s disease is selected from the group consisting of alpha-synuclein, oligomeric alpha-synuclein, phosphorylated alpha- synuclein, and PARK7, and wherein said treatment agent for said Parkinson’s disease is selected from the group consisting of pramipexole (Mirapex), ropinirole (Requip), rotigotine (Neupro), and Amantadine,Attorney Docket No.07039-2255WO1 2022-307 (b) said neurologic disorder is ALS, wherein said biomarker elevated in ATP1A3+EVs of said ALS is selected from the group consisting of Tau, TDP-43, and SOD1, and wherein said treatment agent for said ALS is selected from the group consisting of Qalsody, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta, (c) said neurologic disorder is FTD, wherein said biomarker elevated in ATP1A3+EVs of said FTD is selected from the group consisting of Tau, TDP-43, and phosphorylated TDP-43, and wherein said treatment agent for said FTD is selected from the group consisting of olanzapine (Zyprexa), quetiapine (Seroquel), and trazodone, (d) said neurologic disorder is multiple sclerosis, wherein said biomarker elevated in ATP1A3+EVs of said multiple sclerosis is selected from the group consisting of CCL26, CCL22, and CXCL10, and wherein said treatment agent for said multiple sclerosis is selected from the group consisting of Glatiramer acetate, Ofatumumab, Siponimod, and Cladribine, (e) said neurologic disorder is chronic traumatic encephalopathy, wherein said biomarker elevated in ATP1A3+EVs of said chronic traumatic encephalopathy is selected from the group consisting of Tau, phosphorylated tau, and neurofilament light chain (NEFL), and wherein said treatment agent for said chronic traumatic encephalopathy is selected from the group consisting of Lexapro (escitalopram), Celexa (citalopram), Sinemet (carbidopa / levodopa), Aricept (donepezil), and Namenda (memantine), (f) said neurologic disorder is Huntington’s disease, wherein said biomarker elevated in ATP1A3+EVs of said Huntington’s disease is HTT, and wherein said treatment agent for said Huntington’s disease is selected from the group consisting of Tetrabenazine (Xenazine), deutetrabenazine (Austedo), valbenazine (Ingrezza), and Haloperidol (Haldol), (g) said neurologic disorder is prion disease, wherein said biomarker elevated in ATP1A3+EVs of said prion disease is selected from the group consisting of Tau, phosphorylated tau, and NEFL, and wherein said treatment agent for said prion disease is selected from the group consisting of Quinacrine, Pentosan polysulfate (PPS), and PRN100,Attorney Docket No.07039-2255WO1 2022-307 (h) said neurologic disorder is viral encephalitis, wherein said biomarker elevated in ATP1A3+EVs of said viral encephalitis is selected from the group consisting of IFNG, IL1B, and TNF, and wherein said treatment agent for said viral encephalitis is selected from the group consisting of cyclovir (Zovirax, Sitavig), Ganciclovir, and Foscarnet (Foscavir), (i) said neurologic disorder is cerebrovascular disease, wherein said biomarker elevated in ATP1A3+EVs of said cerebrovascular disease is selected from the group consisting of APOE, SAA1, and VCAM1, and wherein said treatment agent for said cerebrovascular disease is selected from the group consisting of Apixaban (Eliquis), Dabigatran (Pradaxa), Edoxaban (Savaysa), Heparin (various), Rivaroxaban (Xarelto), and Warfarin (Coumadin), or (j) said neurologic disorder is a brain tumor, wherein said biomarker elevated in ATP1A3+EVs of said brain tumor is selected from the group consisting of GFAP, S100B, and VGF, and wherein said treatment agent for said brain tumor is selected from the group consisting of Afinitor Disperz (Everolimus), Avastin (Bevacizumab), Belzutifan, and BiCNU (Carmustine).

95. The method of any one of claims 83 to 94, wherein said mammal was identified as having said ATP1A3+EVs that comprise said presence of said reduced level of said biomarker reduced in ATP1A3+EVs of said neurologic disorder.

96. The method of claim 95, wherein said presence of said reduced level of said biomarker reduced in ATP1A3+EVs of said neurologic disorder was determined using an antibody against said biomarker reduced in ATP1A3+EVs of said neurologic disorder.

97. The method of any one of claims 83 to 96, wherein said neurologic disorder is Alzheimer’s disease (AD).

98. The method of claim 97, wherein said biomarker reduced in ATP1A3+EVs of said AD is selected from the group consisting of ACHE, FABP3, and TREM2.Attorney Docket No.07039-2255WO1 2022-307 99. The method of claim 97 or claim 98, wherein said treatment agent for said AD is selected from the group consisting of cholinesterase inhibitors, lecanemab, donanemab, memantine, and aducanumab.

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