Proton pump binding agent and use thereof in preparing reagent

Abstract

Provided are a proton pump binding agent and use thereof in preparing a reagent. The binding agent comprises a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof.

Description

Proton pump binder and its use in preparing reagents Technical Field The present application relates to the field of biomedicine, and specifically to a proton pump binder and its use in preparing reagents. Background Art Alzheimer's disease (AD) is generally caused by synaptic and neuronal damage, as well as abnormalities in the structure and function of neural circuits. Because the mechanisms of synaptic and neuronal damage remain unclear, progress in effective prevention and treatment of AD has been very slow. The ATP6V1B2 protein, encoded by the ATP6V1B2 gene, is a key structural component of the proton pump driven by ATP hydrolysis. It is widely distributed throughout human tissues, but is more abundant in the brain, kidneys, and osteoclasts. It plays a crucial role in synaptic transmission and lysosomal acidification. Mutations in the gene can cause DOORS syndrome (predisposed autosomal dominant congenital deafness with nail dysplasia syndrome). Reduced ATP6V1B2 protein expression may be associated with the development of AD. Summary of the Invention The present application provides a proton pump binder, which can be used as a potential drug for improving a subject's learning ability, treating cognitive impairment, preventing and / or treating neurodegenerative diseases, and / or preventing and / or treating stroke. The present application provides a binding agent, which comprises a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof, wherein the molecule comprises the amino acid sequence shown in SEQ ID NO: 19 and / or a variant thereof, wherein X is any amino acid. In certain embodiments, the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 20-24 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 25-30 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 31-35 and / or variants thereof. In certain embodiments, the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 36-41 and / or variants thereof. In certain embodiments, the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 42-48 and / or variants thereof. In certain embodiments, the molecules comprise proteins and / or polypeptides. In certain embodiments, the molecule comprises a multimer. In certain embodiments, the multimer comprises a homodimer. In certain embodiments, the cysteine residues in the amino acid sequence of the molecule do not have sulfhydryl blocking modifications. In certain embodiments, the serine in the amino acid sequence of the molecule does not have a phosphorylation modification. In certain embodiments, the molecule comprises a fusion protein and / or a fusion polypeptide. In certain embodiments, the fusion protein and / or fusion polypeptide comprises a molecule capable of being transported across the blood-brain barrier to the brain and / or a molecule capable of crossing a cell membrane. In certain embodiments, the molecule capable of being transported across the blood-brain barrier to the brain and / or the molecule capable of crossing the cell membrane comprises a polypeptide. In certain embodiments, the molecule capable of being transported across the blood-brain barrier to the brain and / or the molecule capable of crossing the cell membrane comprises a cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide comprises an amino acid sequence as shown in any one of SEQ ID NOs: 79-84 and / or variants thereof. In certain embodiments, it comprises an amino acid sequence as shown in any one of SEQ ID NOs: 49-71 and / or variants thereof, wherein X is any amino acid. In certain embodiments, it comprises the amino acid sequence shown in any one of SEQ ID NOs: 72-78 and / or variants thereof. In certain embodiments, the ATP6V1B2 and / or its functionally active fragments are derived from mammals. In certain embodiments, the ATP6V1B2 or a functionally active fragment thereof is derived from human or mouse. In certain embodiments, the ATP6V1B2 comprises the amino acid sequence shown in SEQ ID NO: 8 or 16. In certain embodiments, the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:5. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the human ATP6V1B2 protein. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the mouse ATP6V1B2 protein. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 10-11. In certain embodiments, the ATP6V1B2 comprises an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO. 9 or 17. In certain embodiments, it is capable of modulating proton pump activity and / or function. In certain embodiments, it can increase the expression level and / or activity of a proton pump-related protein in a subject. In certain embodiments, the expression level of the proton pump-associated protein is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. In certain embodiments, the expression level of the proton pump-associated protein is measured by utilizing a substance selected from the following group: a primer capable of specifically amplifying a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a proton pump-associated protein, a small molecule that specifically binds to a proton pump-associated protein, a probe that specifically binds to a proton pump-associated protein, and a polypeptide that specifically binds to a proton pump-associated protein. In certain embodiments, it is capable of regulating the expression level and / or activity of ATP6V1B2. In certain embodiments, it is capable of increasing the expression level and / or activity of ATP6V1B2 in a subject. In certain embodiments, the expression level of ATP6V1B2 includes the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein. In certain embodiments, the increase comprises an increase in the expression level and / or activity of ATP6V1B2 by at least about 10% compared to the expression level and / or activity of native ATP6V1B2 in the subject. In certain embodiments, the expression level of ATP6V1B2 is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. In certain embodiments, the expression level of ATP6V1B2 is measured by utilizing a substance selected from the following group: a primer capable of specifically amplifying the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 protein, a small molecule that specifically binds to the ATP6V1B2 protein, a probe that specifically binds to the ATP6V1B2 protein, and a polypeptide that specifically binds to the ATP6V1B2 protein. In certain embodiments, it is capable of increasing neuronal synaptic transmitter release. In certain embodiments, the increase comprises an increase of at least about 10% compared to the level of synaptic transmitter release from native neurons in the subject. In certain embodiments, it increases the firing frequency of excitatory postsynaptic currents. In certain embodiments, the increase comprises an increase of at least about 10% compared to the level of native excitatory postsynaptic current firing frequency in the subject. In another aspect, the present application provides an isolated polypeptide comprising the amino acid sequence as shown in SEQ ID NO: 19 and / or variants thereof, wherein X is any amino acid. In certain embodiments, it comprises the amino acid sequence shown in any one of SEQ ID NOs: 20-24 and / or variants thereof, wherein X is any amino acid. In certain embodiments, it comprises the amino acid sequence shown in any one of SEQ ID NOs: 25-30 and / or variants thereof, wherein X is any amino acid. In certain embodiments, it comprises the amino acid sequence shown in any one of SEQ ID NOs: 31-35 and / or variants thereof. In certain embodiments, it comprises the amino acid sequence shown in any one of SEQ ID NOs: 36-41 and / or variants thereof. In certain embodiments, it comprises the amino acid sequence shown in any one of SEQ ID NOs: 42-48 and / or variants thereof. On the other hand, the present application provides a fusion polypeptide comprising the polypeptide described in the present application. In certain embodiments, it further comprises molecules capable of being transported across the blood-brain barrier to the brain and / or molecules capable of crossing cell membranes. In certain embodiments, the molecule that is transported across the blood-brain barrier to the brain and / or the molecule that is capable of crossing cell membranes comprises a polypeptide. In certain embodiments, the molecule capable of being transported across the blood-brain barrier to the brain and / or the molecule capable of crossing a cell membrane comprises a cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide comprises an amino acid sequence as shown in any one of SEQ ID NOs: 79-84 or a variant thereof. In certain embodiments, it comprises an amino acid sequence as shown in any one of SEQ ID NOs: 49-71 and / or variants thereof, wherein X is any amino acid. In certain embodiments, it comprises the amino acid sequence shown in any one of SEQ ID NOs: 72-78 and / or variants thereof. On the other hand, the present application provides an immunoconjugate comprising the binding agent described herein, the polypeptide described in the claims of the present application, and / or the fusion polypeptide described herein. In another aspect, the present application provides a nucleic acid molecule encoding the binding agent, the polypeptide and / or the fusion polypeptide described herein. In another aspect, the present application provides a vector comprising the nucleic acid molecule described in the present application. On the other hand, the present application provides a cell comprising the binding agent described herein, the polypeptide or variant thereof described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein and / or the vector described herein. On the other hand, the present application provides a pharmaceutical combination comprising the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein. On the other hand, the present application provides a pharmaceutical composition comprising the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein, and optionally a pharmaceutically acceptable carrier. On the other hand, the present application provides a kit comprising the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein. On the other hand, the present application provides a use of the binding agent described in the present application, the polypeptide described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the drug combination described in the present application and / or the pharmaceutical composition described in the present application in preparing a kit. On the other hand, the present application provides a binding agent described in the present application, a polypeptide described in the present application, a fusion polypeptide described in the present application, an immunoconjugate described in the present application, a nucleic acid molecule described in the present application, a vector described in the present application, a cell described in the present application, a drug combination described in the present application and / or a pharmaceutical composition described in the present application, for use in detecting ATP6V1B2. On the other hand, the present application provides a method for detecting ATP6V1B2 in a sample, which comprises administering the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein, the pharmaceutical composition described herein and / or the kit described herein. On the other hand, the present application provides a use of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in the preparation of a reagent. In certain embodiments, the agent is used to improve learning ability, treat cognitive impairment, prevent and / or treat neurodegenerative diseases, and / or prevent and / or treat stroke. In certain embodiments, the cognitive impairment comprises early cognitive impairment (MCI), moderate cognitive impairment, and severe cognitive impairment. In certain embodiments, the cognitive impairment comprises cognitive impairment caused by normal aging, Lewis body dementia (LBD), frontotemporal dementia and / or vascular dementia. In certain embodiments, the cognitive impairment-inducing disease comprises Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). In certain embodiments, the neurodegenerative disease includes acute neurodegenerative disease and chronic neurodegenerative disease. In certain embodiments, the neurodegenerative disease includes a neurodegenerative disease caused by neuronal death and glial cell homeostasis, a neurodegenerative disease caused by aging, a neurodegenerative disease caused by affected CNS cell function, a neurodegenerative disease caused by abnormal intercellular communication and / or a neurodegenerative disease caused by impaired cell motility. In certain embodiments, the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and / or Huntington's disease (HD). In certain embodiments, the stroke comprises ischemic stroke and / or hemorrhagic stroke. In certain embodiments, the ischemic stroke comprises cerebral infarction. In certain embodiments, the cerebral infarction comprises lacunar infarction, ischemic infarction and / or hemorrhagic infarction. In certain embodiments, the ischemic stroke is caused by factors including thrombosis, embolism and / or hypotension. In certain embodiments, the thrombus is caused by factors including atherosclerosis, aneurysm, vascular malformation, arteritis and / or vasospasm. In certain embodiments, the hemorrhagic stroke comprises intraparenchymal hemorrhage, intraventricular hemorrhage and / or subarachnoid hemorrhage. In certain embodiments, the hemorrhagic stroke includes primary cerebral hemorrhage and / or secondary cerebral hemorrhage. In certain embodiments, the hemorrhagic stroke comprises an aneurysmal subarachnoid hemorrhage. In certain embodiments, the hemorrhagic stroke is caused by factors including: vascular malformation, aneurysm, blood disease, cerebral amyloid angiopathy, abnormal vascular network at the base of the brain, cerebral arteritis, anticoagulant or thrombolytic therapy and / or tumor stroke. In certain embodiments, the stroke comprises damage caused by the stroke. In certain embodiments, the lesions comprise lesions observed by imaging. In certain embodiments, the lesions observed by imaging include intracerebral hematoma, intraventricular hemorrhage and / or subarachnoid hemorrhage. In certain embodiments, the lesions observed by imaging include edema, hematoma and / or mass effect. In certain embodiments, the lesions observed by imaging include dense artery sign, island band sign, blurred outline or decreased density of the lenticular nucleus, occlusion of cerebral perforating arterioles, edema and / or mass. In certain embodiments, the impairment comprises an impairment in learning ability. In certain embodiments, the learning ability comprises cognitive ability, motor ability, memory ability and / or spatial exploration ability. In certain embodiments, the improvement in learning ability comprises an improvement in the subject's learning ability assessment score by at least about 50% compared to the subject's original learning ability assessment score. In certain embodiments, the assessment score of learning ability is measured by performing a test selected from the group consisting of a novel object recognition test and a water maze test. In certain embodiments, the novel object recognition test assesses the cognitive ability, motor ability and / or spatial exploration ability. In certain embodiments, the water maze test evaluates the memory ability, motor ability and / or spatial exploration ability. In certain embodiments, the subject comprises a mammal. In certain embodiments, the subject comprises a human. In certain embodiments, the subject comprises a non-cognitive disorder patient, a non-neurodegenerative disease patient, and / or a non-stroke patient. In certain embodiments, the subject comprises a patient with cognitive impairment, a patient with a neurodegenerative disease, and / or a patient with a stroke. In certain embodiments, the subject comprises an Alzheimer's disease patient. In certain embodiments, the subject is elderly. In certain embodiments, the agent is formulated for oral administration and / or injection. In certain embodiments, the agent is formulated for intravenous injection. On the other hand, the present application provides a binding agent described herein, a polypeptide described herein, a fusion polypeptide described herein, an immunoconjugate described herein, a nucleic acid molecule described herein, a vector described herein, a cell described herein, a drug combination described herein and / or a pharmaceutical composition described herein for improving learning ability, treating cognitive disorders, treating neurodegenerative diseases, preventing and / or treating stroke. On the other hand, the present application provides a method for improving learning ability, treating cognitive disorders, treating neurodegenerative diseases, preventing and / or treating stroke, which comprises administering the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein to a subject in need. On the other hand, the present application provides a binding agent comprising two parts, wherein the first part comprises a molecule that binds to ATP6V1B2 and / or a functionally active fragment thereof, and the second part comprises a molecule that delivers the first part. In certain embodiments, the second portion functions to deliver the first portion into cells and / or transport it across the blood-brain barrier to the brain. In certain embodiments, the second moiety is capable of delivering the first moiety into a cell expressing ATP6V1B2. In certain embodiments, the second moiety comprises a modifying group, a small molecule, a nanoparticle, an exosome, a virus, a nucleic acid, a protein and / or a polypeptide. In certain embodiments, the second portion includes a group for PEGylation, lipidation, and / or glycosylation of the first portion. In certain embodiments, the nanoparticles comprise liposomes. In certain embodiments, the liposomes include modified liposomes, and the modifications include polypeptide modification, antibody modification, glycosyl modification, ligand modification, nucleic acid aptamer and / or multi-targeting modification. In certain embodiments, the second moiety comprises a molecule that interferes with the physiological barrier function of the blood-brain barrier and / or a binding agent for a transporter protein on the blood-brain barrier. In certain embodiments, the molecule that interferes with the physiological barrier function of the blood-brain barrier comprises an efflux inhibitor. In certain embodiments, the transport proteins on the blood-brain barrier include insulin receptor (IR), transferrin receptor (TfR), low density lipoprotein receptor (LDLR), low density lipoprotein receptor-related protein 1 (LRP1) and LRP2, and diphtheria toxin receptor (DTR). In certain embodiments, the second moiety comprises a blood-brain barrier transporter binding protein. In certain embodiments, the second portion comprises an antibody and / or an antigen-binding fragment thereof that targets a transporter protein on the blood-brain barrier. In certain embodiments, the second portion comprises an antibody and / or an antigen-binding fragment thereof that targets transferrin receptor. In certain embodiments, the second moiety comprises a binding agent for a protein that mediates endocytosis. In certain embodiments, the second moiety comprises a cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide includes a cell-penetrating peptide that enters the cell via endocytosis and / or direct penetration. In certain embodiments, the cell-penetrating peptide comprises: a cationic cell-penetrating peptide, an amphipathic cell-penetrating peptide and / or a hydrophobic cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide comprises a linear peptide and / or a cyclic peptide. In certain embodiments, the cell-penetrating peptide comprises a cell-penetrating peptide derived from TAT protein. In certain embodiments, the second portion comprises the amino acid sequence shown in SEQ ID NO: 79 and / or its variants. In certain embodiments, the second portion comprises the amino acid sequence shown in any one of SEQ ID NOs: 80-84 and / or variants thereof. In certain embodiments, the first portion is connected to the second portion. In certain embodiments, the first portion is directly or indirectly connected to the second portion. In certain embodiments, the first portion comprises an amino acid sequence as shown in any one of SEQ ID NOs: 19-30, SEQ ID NOs: 93-99, and / or variants thereof, wherein X is any amino acid. In certain embodiments, the first portion comprises the amino acid sequence shown in any one of SEQ ID NOs: 31-48, SEQ ID NOs: 86-92 and / or variants thereof. In certain embodiments, the first portion comprises the amino acid sequence shown in SEQ ID NO: 85 and / or its variants. In certain embodiments, the first portion comprises a protein and / or a polypeptide. In certain embodiments, the first portion comprises a polymer. In certain embodiments, the multimer comprises a homodimer. In certain embodiments, the cysteine in the first amino acid sequence does not have a thiol-blocking modification. In certain embodiments, the serine in the first amino acid sequence does not have a phosphorylation modification. In certain embodiments, the first portion and the second portion form a fusion polypeptide. In certain embodiments, the binding agent comprises the amino acid sequence shown in any one of SEQ ID NOs: 100-104 and / or variants thereof. In certain embodiments, the ATP6V1B2 and / or its functionally active fragments are derived from mammals. In certain embodiments, the ATP6V1B2 or a functionally active fragment thereof is derived from human or mouse. In certain embodiments, the ATP6V1B2 comprises the amino acid sequence shown in SEQ ID NO: 8 or 16. In certain embodiments, the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:5. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the human ATP6V1B2 protein. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the mouse ATP6V1B2 protein. In certain embodiments, the functionally active fragment of ATP6V1B2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 10-11. In certain embodiments, the ATP6V1B2 comprises an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO. 9 or 17. In certain embodiments, it is capable of modulating proton pump activity and / or function. In certain embodiments, it can increase the expression level and / or activity of a proton pump-related protein in a subject. In certain embodiments, the expression level of the proton pump-associated protein is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. In certain embodiments, the expression level of the proton pump-associated protein is measured by utilizing a substance selected from the following group: a primer capable of specifically amplifying a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a proton pump-associated protein, a small molecule that specifically binds to a proton pump-associated protein, a probe that specifically binds to a proton pump-associated protein, and a polypeptide that specifically binds to a proton pump-associated protein. In certain embodiments, it is capable of regulating the expression level and / or activity of ATP6V1B2. In certain embodiments, it is capable of increasing the expression level and / or activity of ATP6V1B2 in a subject. In certain embodiments, the expression level of ATP6V1B2 includes the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein. In certain embodiments, the increase comprises an increase in the expression level and / or activity of ATP6V1B2 by at least about 10% compared to the expression level and / or activity of native ATP6V1B2 in the subject. In certain embodiments, the expression level of ATP6V1B2 is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. In certain embodiments, the expression level of ATP6V1B2 is measured by utilizing a substance selected from the following group: a primer capable of specifically amplifying the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 protein, a small molecule that specifically binds to the ATP6V1B2 protein, a probe that specifically binds to the ATP6V1B2 protein, and a polypeptide that specifically binds to the ATP6V1B2 protein. In certain embodiments, it is capable of increasing neuronal synaptic transmitter release. In certain embodiments, the increase comprises an increase of at least about 10% compared to the level of synaptic transmitter release from native neurons in the subject. In certain embodiments, it increases the firing frequency of excitatory postsynaptic currents. In certain embodiments, the increase comprises an increase of at least about 10% compared to the level of native excitatory postsynaptic current firing frequency in the subject. On the other hand, the present application provides a fusion polypeptide comprising an amino acid sequence shown in any one of SEQ ID NOs: 100-104, wherein X is any amino acid. In certain embodiments, the fusion polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 100-104. In another aspect, the present application provides an immunoconjugate comprising the binding agent described herein and / or the fusion polypeptide described herein. In another aspect, the present application provides a nucleic acid molecule encoding the binding agent and / or the fusion polypeptide described in the present application. In another aspect, the present application provides a vector comprising the nucleic acid molecule described in the present application. On the other hand, the present application provides a cell comprising the binding agent or variant thereof described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein and / or the vector described herein. On the other hand, the present application provides a pharmaceutical combination comprising the binding agent described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein. On the other hand, the present application provides a pharmaceutical composition comprising the binding agent described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein, and optionally a pharmaceutically acceptable carrier. On the other hand, the present application provides a kit comprising the binding agent described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein. On the other hand, the present application provides a use of the binding agent described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the drug combination described in the present application and / or the pharmaceutical composition described in the present application in preparing a kit. On the other hand, the present application provides a binding agent described in the present application, a fusion polypeptide described in the present application, an immunoconjugate described in the present application, a nucleic acid molecule described in the present application, a vector described in the present application, a cell described in the present application, a drug combination described in the present application, a pharmaceutical composition described in the present application and / or a kit described in the present application, for use in detecting ATP6V1B2. On the other hand, the present application provides a method for detecting ATP6V1B2 in a sample, which comprises administering the binding agent described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein, the pharmaceutical composition described herein and / or the kit described herein. On the other hand, the present application provides a use of the binding agent described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the drug combination described in the present application and / or the pharmaceutical composition described in the present application in the preparation of a reagent. In certain embodiments, the agent is used to improve learning ability, treat cognitive impairment, prevent and / or treat neurodegenerative diseases, and / or prevent and / or treat stroke. In certain embodiments, the cognitive impairment comprises early cognitive impairment (MCI), moderate cognitive impairment, and severe cognitive impairment. In certain embodiments, the cognitive impairment comprises cognitive impairment caused by normal aging, Lewis body dementia (LBD), frontotemporal dementia and / or vascular dementia. In certain embodiments, the cognitive impairment-inducing disease comprises Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). In certain embodiments, the neurodegenerative disease includes acute neurodegenerative disease and chronic neurodegenerative disease. In certain embodiments, the neurodegenerative disease includes a neurodegenerative disease caused by neuronal death and glial cell homeostasis, a neurodegenerative disease caused by aging, a neurodegenerative disease caused by affected CNS cell function, a neurodegenerative disease caused by abnormal intercellular communication and / or a neurodegenerative disease caused by impaired cell motility. In certain embodiments, the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and / or Huntington's disease (HD). In certain embodiments, the stroke comprises ischemic stroke and / or hemorrhagic stroke. In certain embodiments, the ischemic stroke comprises cerebral infarction. In certain embodiments, the cerebral infarction comprises lacunar infarction, ischemic infarction and / or hemorrhagic infarction. In certain embodiments, the ischemic stroke is caused by factors including thrombosis, embolism and / or hypotension. In certain embodiments, the thrombus is caused by factors including atherosclerosis, aneurysm, vascular malformation, arteritis and / or vasospasm. In certain embodiments, the hemorrhagic stroke comprises intraparenchymal hemorrhage, intraventricular hemorrhage and / or subarachnoid hemorrhage. In certain embodiments, the hemorrhagic stroke includes primary cerebral hemorrhage and / or secondary cerebral hemorrhage. In certain embodiments, the hemorrhagic stroke comprises an aneurysmal subarachnoid hemorrhage. In certain embodiments, the hemorrhagic stroke is caused by factors including: vascular malformation, aneurysm, blood disease, cerebral amyloid angiopathy, abnormal vascular network at the base of the brain, cerebral arteritis, anticoagulant or thrombolytic therapy and / or tumor stroke. In certain embodiments, the stroke comprises damage caused by the stroke. In certain embodiments, the lesions comprise lesions observed by imaging. In certain embodiments, the lesions observed by imaging include intracerebral hematoma, intraventricular hemorrhage and / or subarachnoid hemorrhage. In certain embodiments, the lesions observed by imaging include edema, hematoma and / or mass effect. In certain embodiments, the lesions observed by imaging include dense artery sign, island band sign, blurred outline or decreased density of the lenticular nucleus, occlusion of cerebral perforating arterioles, edema and / or mass. In certain embodiments, the impairment comprises an impairment in learning ability. In certain embodiments, the learning ability comprises cognitive ability, motor ability, memory ability and / or spatial exploration ability. In certain embodiments, the improvement in learning ability comprises an improvement in the subject's learning ability assessment score by at least about 50% compared to the subject's original learning ability assessment score. In certain embodiments, the assessment score of learning ability is measured by performing a test selected from the group consisting of a novel object recognition test and a water maze test. In certain embodiments, the novel object recognition test assesses the cognitive ability, motor ability and / or spatial exploration ability. In certain embodiments, the water maze test evaluates the memory ability, motor ability and / or spatial exploration ability. In certain embodiments, the subject comprises a mammal. In certain embodiments, the subject comprises a human. In certain embodiments, the subject comprises a non-cognitive disorder patient, a non-neurodegenerative disease patient, and / or a non-stroke patient. In certain embodiments, the subject comprises a patient with cognitive impairment, a patient with a neurodegenerative disease, and / or a patient with a stroke. In certain embodiments, the subject comprises an Alzheimer's disease patient. In certain embodiments, the subject is elderly. In certain embodiments, the agent is formulated for oral administration and / or injection. In certain embodiments, the agent is formulated for intravenous injection. On the other hand, the present application provides a use of the binding agent described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in improving learning ability, treating cognitive disorders, treating neurodegenerative diseases, and preventing and / or treating stroke. On the other hand, the present application provides a method for improving learning ability, treating cognitive disorders, treating neurodegenerative diseases, preventing and / or treating stroke, which comprises administering the binding agent described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein to a subject in need. Those skilled in the art can easily discern other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of this application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application relates. Accordingly, the descriptions in the drawings and specification of this application are merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS The specific features of the invention involved in this application are shown in the appended claims. The features and advantages of the invention involved in this application can be better understood by referring to the exemplary embodiments described in detail below and the accompanying drawings. A brief description of the drawings is as follows: FIG1 shows the results of immunoprecipitation of ATP6V1B2 protein by the ATP6V1B2 binding agent described in the present application. FIG2 shows the effect of the ATP6V1B2 binder of the present application on spontaneous excitatory postsynaptic current. FIG3 shows the effect of the ATP6V1B2 binder of the present application on spontaneous excitatory postsynaptic current. Figure 4 shows the effects of ATP6V1B2 binders on lysosomal acidity. DETAILED DESCRIPTION The following describes the implementation of the present invention through specific embodiments. People familiar with this technology can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Definition of terms In this application, the term "binding agent" generally refers to a natural or non-natural molecule that specifically binds to a target or a portion of a target. Binding agents can include small molecule compounds, polymers, and / or biomacromolecules. Binding agents can include proteins, peptides, nucleic acids, sugars, lipids, and small molecule compounds. For example, a binding agent can include a polypeptide. For example, a binding agent can include a fusion polypeptide. In this application, the term "ATP6V1B2" generally refers to the ATPase H+ transporting V1 subunit B2 protein (or ATPase H+ transporting V1 subunit B2) (or ATP6B2, DOOD, HO57, VATB, VPP3, Vma2 or ZLS2), and the gene encoding the protein. The ATP6V1B2 can be a multi-subunit enzyme that mediates acidification of organelles in eukaryotic cells. The ATP6V1B2 can affect the acidity of lysosomes. The ATP6V1B2 can participate in processes such as protein sorting, zymogen activation, receptor-mediated endocytosis and synaptic vesicle proton gradient generation. The ATP6V1B2 protein can include a cytoplasmic V1 domain and a transmembrane V0 domain. The accession number of human ATP6V1B2 in GenBank is 526. The accession number of human ATP6V1B2 in UniProt can be P21281. In this application, the term "proton pump-associated protein" generally refers to proteins that encode and / or express proton pumps. The proton pumps can be proteins that actively transport hydrogen ions across a biological membrane against the electrochemical potential difference between hydrogen ions on either side of the membrane. These proton pumps can include Na-K pumps, Ca2+ pumps, H+-ATP pumps, and H+ pyrophosphate pumps. In the present application, the term "expression level" generally refers to the protein, RNA or mRNA level of a specific related gene. Any method known in the art can be used to measure the expression level of a specific related gene (such as human ATP6V1B2 gene). In the present application, "expression" generally refers to the process by which the information encoded by a gene is converted into a structure present in a cell and operated in a cell. For example, reverse transcription and amplification analysis (such as PCR, connection RT-PCR or quantitative RT-PCR), hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining or mass spectrometry can be included. Analysis can be performed directly on a biological sample or on the protein / nucleic acid separated from the sample. In this application, the term "activity" generally refers to any activity associated with a particular protein. In this application, the activity may include, for example, any activity associated with the ATP6V1B2 protein. The activity may include an enzymatic activity associated with a protease. In some cases, the activity may include a biological activity. In some cases, the activity may include binding of the protein to a receptor, for example, where the binding may produce a measurable downstream effect. In this application, the activity may include any activity that would be attributed to the protein by one skilled in the art. In this application, the term "variant" generally refers to a polypeptide comprising an amino acid sequence that differs from the amino acid sequence of a parent or reference polypeptide (e.g., a wild-type polypeptide) by at least one amino acid residue. In this application, the variant may have a higher (e.g., at least 80%) homology with the parent or reference polypeptide. The homology may include sequence similarity or identity. In this application, the homology may be determined using standard techniques known in the art (see, for example, Smith and Waterman, Adv. Appl. Math. Advances in Applied Mathematics); the percentage of identity shared by polynucleotide or polypeptide sequences is determined by direct comparison of sequence information between molecules, the comparison being performed by sequence alignment and determining identity using methods known in the art. An example of an algorithm suitable for determining sequence similarity is the BLAST algorithm (see Altschul et al., J. Mol. Biol., 215: 403-410).

[1990] ). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (NCBI). In the present application, the "variant" and / or "functional variant" can be, for example, a protein or polypeptide in which one or more amino acids are substituted, deleted or added in the amino acid sequence of the protein and / or the polypeptide (e.g., a binder that binds to ATP6V1B2 or a fragment thereof). For example, the variant may comprise a protein or polypeptide that has been subjected to amino acid changes by at least 1, for example, 1-30, 1-20 or 1-10, for example, 1, 2, 3, 4 or 5 amino acid substitutions, deletions and / or insertions. The functional variant may substantially retain the biological properties of the protein or polypeptide before the change (e.g., substitution, deletion or addition). For example, the functional variant may retain at least 60%, 70%, 80%, 90%, or 100% of the biological activity (e.g., the ability to bind to ATP6V1B2) of the protein or polypeptide before the change. For example, the substitution may be a conservative substitution. For example, the variant may also be a polypeptide encompassing its functionally active fragments, and is not limited to polypeptides comprising the functionally active fragments of the protein produced after processing and / or modification in the cell. In the present application, the "variant" may be a homolog. The homolog may be a protein or polypeptide having at least about 85% (e.g., at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence of the protein and / or polypeptide (e.g., a binding agent that specifically binds to ATP6V1B2 or a fragment thereof). In the present application, described homology generally refers to the similarity, similarity or association between two or more sequences.Can calculate " sequence homology per-cent " in the following manner: two sequences to be compared are compared in comparison window, determine that there is identical nucleic acid base (for example, A, T, C, G, U) or identical amino acid residue (for example, Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) number in the position to obtain the number of matching positions, with the number of matching positions divided by the total number of positions (that is, window size) in the comparison window, and result is multiplied by 100, to produce sequence homology per-cent.Comparison carried out in order to determine the sequence homology per-cent, can realize by several ways known in the art, for example, use publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximum alignment over the full length of the sequences being compared or within a region of interest. Homology can also be determined by the following methods: FASTA and BLAST. A description of the FASTA algorithm can be found in W. R. Earson and D. J. Lipman, "Improved tools for biological sequence comparison," Proc. Natl. Acad. Sci., 85: 2444-2448, 1988; and D. J. Lipman and W. R. Earson, "Rapid and sensitive protein similarity search," Science, 227: 1435-1441, 1989. A description of the BLAST algorithm can be found in S. Altschul, W. Gish, W. Miller, E. W. Myers, and D. Lipman, "A basic local alignment search tool," J. Mol. Biol., 215: 403-410, 1990. In this application, the term "amino acid" generally refers to naturally occurring, synthetic, or non-natural amino acids, as well as amino acid analogs and amino acid mimetics that function in a similar manner to naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; analogs, derivatives, and congeners thereof; amino acid analogs with variant side chains; and stereoisomers of any of the foregoing. The 20 commonly used amino acids and their abbreviations used in this application are conventionally used. See Immunology-A Synthesis (2nd edition, ES Golub and DR Gren, eds., Sinauer Associates, Sunderland, Mass. (1991)), the contents of which are incorporated herein by reference. This application uses commonly used amino acid single-letter abbreviations and three-letter abbreviations (Bruce Alberts et al., Molecular Biology of the Cell, Garland Publishing, Inc., New York (4th edition, 2002)). In this application, the term "conservative replacement" or "conservative substitution", also known as "conservative mutation", generally refers to the substitution of an amino acid with another amino acid having similar properties (such as charge, side chain size, hydrophobicity / hydrophilicity, main chain conformation and rigidity, etc.) in a protein. Examples of amino acid groups having side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxy side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine and tryptophan; 5) basic side chains: lysine, arginine and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine and methionine. Conservative amino acid substitution groups can be, for example, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. In this application, the term "non-conservative substitution" is also referred to as "radical replacement" or "radical substitution", which generally refers to the substitution of an amino acid with another amino acid having different properties in the protein (e.g., charge, side chain size, hydrophobicity / hydrophilicity, main chain conformation and rigidity, etc.). For example, non-conservative substitution can also involve the use of unnatural amino acids. In the present application, the term "polar amino acid" can include polar uncharged amino acids, basic (positively charged) amino acids, acidic (negatively charged) amino acids. For example, polar amino acids can include threonine, serine, cystine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid. In the present application, the term "non-polar amino acids" may include phenylalanine, proline, valine, leucine, isoleucine, methionine, tryptophan, alanine, glycine. In the present application, the term "fusion polypeptide" generally refers to a polypeptide that comprises at least two discrete peptides or polypeptides (which do not exist together in this way in natural polypeptides, that is, these parts do not naturally exist in the same polypeptide or in the same order), or is composed of at least two discrete peptides or polypeptides (which do not exist together in this way in natural polypeptides, that is, these parts do not naturally exist in the same polypeptide or in the same order). The discrete peptides or polypeptides can be linked together directly or indirectly to form a fusion polypeptide. For example, the discrete peptides or polypeptides can be linked to form a fusion polypeptide by peptide bonds. For example, the discrete peptides or polypeptides can be linked to form a fusion polypeptide by a linker. For example, the fusion polypeptide described in the present application may include a fusion polypeptide formed by connecting a polypeptide capable of binding to ATP6V1B2 and a polypeptide having a specific function. In the present application, the term "fusion protein" generally refers to a protein composed of two or more polypeptides. In this application, the term "blood-brain barrier (BBB)" generally refers to the physiological barrier between peripheral circulation and the brain and spinal cord, which is composed of the end feet of brain capillary endothelial cells, basement membranes, and glial cells, forming a tight barrier that limits molecules, even very small molecules (such as urea (60 daltons)) to be transported to the brain. The BBB in the brain, the blood-spinal cord barrier in the spinal cord, and the blood-retinal barrier in the retina are continuous capillary barriers in the CNS, and are collectively referred to as blood-brain barrier or BBB in this article. The BBB also encompasses blood-CSF barrier (choroid plexus), wherein the barrier is composed of ependymal cells rather than capillary endothelial cells. The physiological barrier function of the blood-brain barrier can include selectively preventing certain substances from entering the brain by the blood and / or selectively pumping harmful or excess substances in the brain out of the brain. There are multiple transporters on the blood-brain barrier. For example, transport proteins on the blood-brain barrier can include, but are not limited to, insulin receptor (IR), transferrin receptor (TfR), low density lipoprotein receptor (LDLR), low density lipoprotein receptor-related protein 1 (LRP1) and LRP2, and / or diphtheria toxin receptor (DTR). In this application, the term "endocytosis," also known as "endocytosis" or "entocytosis," generally refers to the method by which a substance enters a cell. The term "endocytosis" as used herein may include various mechanisms by which a substance enters a cell. For example, the term "endocytosis" may include phagocytosis, pinocytosis, and / or receptor-mediated endocytosis. The term "protein mediating endocytosis" as used herein generally refers to proteins and / or polypeptide molecules involved in the endocytic process. In this application, the term "membrane-penetrating peptide" generally refers to a class of short peptides that can cross cell membranes or tissue barriers. For example, membrane-penetrating peptides can carry biomacromolecules such as proteins, RNA, and DNA into cells through mechanisms such as endocytosis and direct penetration to exert their effector functions. Membrane-penetrating peptides related to the endocytic mechanism may involve multiple cellular endocytosis pathways. The direct membrane-penetrating mechanism is usually because the membrane-penetrating peptide causes perturbation and instability of the cell membrane, thereby changing the permeability of the cell membrane. Based on the physicochemical properties of membrane-penetrating peptides, membrane-penetrating peptides can be divided into three categories: cationic, amphiphilic, and hydrophobic. Cationic cell-penetrating peptides generally have a high net positive charge. Amphiphilic cell-penetrating peptides generally contain both polar and non-polar groups, thus possessing both hydrophilic and hydrophobic properties. Hydrophobic cell-penetrating peptides generally contain only non-polar groups and therefore have a lower net charge. In this application, the term "polymer" generally refers to a molecule having two or more polypeptide chains associated by covalent, non-covalent, or both covalent and non-covalent interactions. The polymer may include a dimer. In this application, the term "homodimer" generally refers to a molecule formed by two identical monomers. These two identical monomers can aggregate, complex or associate with each other through covalent and / or non-covalent interactions. In this application, the term "sulfhydryl blocking" generally refers to blocking free sulfhydryl groups to prevent the formation of intramolecular and / or intermolecular disulfide bonds. In this application, the sulfhydryl blocking can occur on cysteine residues. The sulfhydryl blocking can prevent the formation of disulfide bonds between cysteine residues of the protein, thereby preventing the protein from being cross-linked or modified. The sulfhydryl blocking can be achieved by using a blocking agent, which can be a reducing agent. The blocking agent can include dithiothreitol (DTT), β-mercaptoethanol (BME), and tris(2-carboxyethyl)phosphine hydrochloride (TCEP·HCl). In this application, the term "serine phosphorylation" generally refers to a phosphorylation modification that occurs on a serine residue. The serine phosphorylation can be a process in which a phosphate group from a donor (e.g., ATP or GTP) is transferred to a serine residue. The serine phosphorylation can be mediated by a protein kinase. The serine phosphorylation can result in changes in protein activity. In this application, the term "isolated" generally refers to a substance obtained artificially from its natural state. For example, a polynucleotide or polypeptide naturally present in a living animal, which has not been isolated, and a highly purified identical polynucleotide or polypeptide isolated from this natural state can be considered isolated. The term "isolated" does not exclude the presence of artificial or synthetic substances, nor does it exclude the presence of other impurities that do not affect the activity of the substance. In this application, the term "nucleic acid molecule" generally refers to isolated forms of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof, isolated from their natural environment or artificially synthesized. In this application, the term "vector" generally refers to a nucleic acid delivery vehicle into which a polynucleotide encoding a protein can be inserted and used to express the protein. A vector can transform, transduce, or transfect host cells, allowing the genetic material it carries to be expressed within the host cells. A single vector may contain multiple elements that control expression. Furthermore, a vector may contain an origin of replication. A vector may also include components that facilitate its entry into cells. In this application, the term "cell" generally refers to a single cell, cell line or cell culture that may be or has been a recipient of a subject's plasmid or vector, including a nucleic acid molecule as described herein or a vector as described herein. A cell may include the offspring of a single cell. Due to natural, accidental or intentional mutations, the offspring may not necessarily be identical to the original parent cell (in terms of the morphology of the total DNA complement or in the genome). A cell may include a cell transfected in vitro with a vector as described herein. In this application, the term "immunoconjugate" generally refers to a substance formed by linking a polypeptide with other active agents, which may be small molecule active agents, such as therapeutic agents, imaging probes, or spectroscopic probes. In this application, the term "pharmaceutical composition" generally refers to a composition for preventing / treating a disease or condition. The pharmaceutical composition may comprise the binding agent described herein, the isolated polypeptide described herein, the fusion polypeptide described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein, and optionally a pharmaceutically acceptable adjuvant. In addition, the pharmaceutical composition may further comprise one or more (pharmaceutically effective) carriers and other suitable formulations. The acceptable ingredients of the composition may be non-toxic to the recipient at the dosage and concentration used. The pharmaceutical composition of the present application includes, but is not limited to, liquid, frozen and lyophilized compositions. In this application, the term "pharmaceutically acceptable carrier" generally refers to a pharmaceutically acceptable carrier, excipient, or stabilizer that is non-toxic to cells or mammals exposed thereto at the doses and concentrations employed. Physiologically acceptable carriers may include suitable substances. Pharmaceutically acceptable carriers are generally not the same substance as vectors used to insert nucleic acids in genetic engineering. In this application, the term "specific binding" or "specific" generally refers to a measurable and reproducible interaction, such as binding between a target and an antibody, that can determine the presence of a target in the presence of a heterogeneous population of molecules (including biomolecules). For example, an antibody that specifically binds to a target (which may be an epitope) may be one that binds to that target with greater affinity, avidity, more readily, and / or for a greater duration than it binds to other targets. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among proteins of different species. In certain embodiments, specific binding may include, but does not require, exclusive binding. In this application, the term "transmitter release" generally refers to neurotransmitter release, that is, a neuron releases a neurotransmitter (Neurotransmitter) encapsulated in a vesicle into the synaptic cleft, which acts on another neuron to transmit information. In the transmitter release process, the basic structure of the neural circuit, the synapse (Synapse), may be involved. In some cases, the transmitter release can be referred to as synaptic transmission (Synaptic transmission). The method of transmitter release can include synchronous release (Synchronous release), asynchronous release (Asynchronous release) and spontaneous release (Spontaneous release). In this application, the term "discharge frequency" generally refers to the discharge frequency of action potentials. Action potential can refer to the rapid and reversible reversal and recovery process of the potential on both sides of the membrane generated on the basis of the resting potential when an excitable cell is stimulated. The action potential can be composed of a peak potential and an afterpotential, corresponding to the depolarization (Depolarisation) and hyperpolarization (Hyperpolarization) processes respectively. The discharge of action potentials can have the characteristics of pulses. In some cases, the discharge frequency of pulses is the ratio of the number of pulse discharges to the time. For example, the discharge frequency can include the discharge frequency of synaptic vesicles releasing neurotransmitters. For example, the discharge frequency can include the discharge frequency of excitatory postsynaptic currents. In this application, the term "neuron" generally refers to a nerve cell, which is the main functional unit of the nervous system. A neuron can be composed of a cell body and its protrusions, an axon, and one or more dendrites. Neurons can transmit information to other neurons or cells by releasing neurotransmitters at synapses. In this application, the term "learning ability" generally refers to all abilities related to or required for the learning / cognitive process. Such learning ability may include the ability to acquire new information, knowledge, and / or skills through processes such as experience, learning, or training. Such learning ability may include imagination, attention, perceptual observation, reading ability, analytical ability, operational ability, adaptability, summarization, problem-solving ability, or a combination thereof. In this application, the term "cognitive ability" generally refers to the ability to process information through perception. This cognitive ability may include the ability to grasp the composition of things, their performance and relationship with other things, the driving force of development, the direction of development, and the basic laws. In this application, the term "athletic ability" generally refers to the ability to participate in sports and training. Athletic ability can include aerobic fitness, muscle strength, body flexibility, balance, and reaction ability. Athletic ability can be a comprehensive manifestation of multiple factors such as physical shape, quality, skills, techniques, and psychological ability. In this application, the term "memory ability" generally refers to the ability to recognize, retain, re-recognize and reproduce the content and experience reflected by objective things. The memory ability can include sensory memory ability, short-term memory ability and long-term memory ability. In this application, the term "spatial exploration ability" generally refers to the ability to explore the shape and / or position of an object. The spatial exploration ability includes observing, thinking, imagining, recognizing and / or exploring the shape and / or position of an object. In this application, the term "assessment score of learning ability" generally refers to a quantitative assessment score of a subject's learning ability. The assessment score of the learning ability can be obtained by performing an assessment including attention / executive function (such as Wechsler Memory Test), language ability assessment (such as language screening test (the language screening test, LAST)), visual space and structural ability assessment (such as visual motor integration test, Hooper visual organization test, article patchwork test, graphic arrangement test, clock drawing test), application ability assessment, daily function assessment (such as dementia disability assessment (disability assessment for dementia, DAD)) and / or the score obtained by the neuropsychological scale. In some cases, the assessment score of the learning ability can be obtained by performing a mini-mental state examination (mini-mental state examination, MMSE), Montreal cognitive assessment scale (Montreal cognitive assessment, MoCA), Alzheimer's disease assessment scale-cognitive part (Alzheimer disease assessment scale-cog, ADAS-cog) and clinical dementia rating scale (clinical dementia rating scale, CDR) detection. In the present application, the term "novel object recognition test" generally refers to a test in which an animal (e.g., a mouse) is made to recognize an object in a specific space to detect the time required for the animal to learn to recognize a new object. In some cases, the novel object recognition test can refer to the test method described in Ennaceur et al., Behav Brain Res 80 9-25, 1996. For example, the novel object recognition test may comprise the following steps: two identical objects are placed in a container of fixed volume, a mouse is placed in the container to recognize the two objects, and after a period of time, one of the two objects in the same container is replaced with a new object with a different shape, and then the mouse's search time for the new object is measured. In this application, the term "water maze test" generally refers to a test in which an animal (e.g., a mouse) is forced to swim, thereby learning to find a platform hidden in the water. The water maze test (e.g., Morris water maze) can test a mouse's learning ability and / or memory ability for a sense of spatial position and direction. The water maze test can also include acquisition training, exploratory training, counterpoint training, or counterpoint exploratory training. If the time required for an animal (e.g., a mouse) to find a platform from entering the water is shorter, and the distance moved during this period is approximately shorter, the assessment score for the animal's (e.g., mouse's) learning ability is correspondingly approximately higher. The water maze evaluation test can be an important experiment for evaluating learning ability. In this application, the term "neurodegenerative disease" generally refers to cognitive disorders such as dementia caused by the gradual loss of neuronal structure and function, including neuronal death and glial cell imbalance. In some cases, age (e.g., Alzheimer's disease (AD), Parkinson's disease (PD)) or genetic mutations that affect CNS cell function (e.g., Huntington's disease, early-onset AD or PD, amyotrophic lateral sclerosis (ALS)) can cause the neurodegenerative disease. The neurodegenerative disease may have changes and / or conditions selected from the following: protein misfolding and aggregation; neuroinflammation (e.g., CNS inflammation that occurs under toxic stimulation (e.g., protein aggregation), infection, traumatic injury, or autoimmunity); changes in cell signal transduction; acquired aging / cell death (e.g., interrupted apoptosis signal transduction, mitochondrial dysfunction, impaired autophagy, and necrotic bodies activated by stress / inflammation); motor cell damage and epigenetic changes. In this application, the term "Alzheimer's disease" generally refers to precocious dementia, senile dementia, a neurodegenerative disease with a slow progression of disease that worsens over time. The most common early symptom is loss of short-term memory (difficulty remembering recent events). As the disease progresses, at least one of the following symptoms may gradually appear: language disorders, disorientation (e.g., easily getting lost), emotional instability, loss of motivation, inability to take care of oneself, and behavioral problems. The true cause of Alzheimer's disease is still unknown, and its progression may be related to the deposition of amyloid plaques in the brain and fibrillary tangles caused by hyperphosphorylation of Tau proteins. There is currently no treatment that can prevent or reverse the course of the disease, and only a few methods may temporarily relieve or improve symptoms. In this application, the terms "early cognitive impairment (MCI)" and "mild cognitive impairment" are used interchangeably and generally refer to a clinical state intermediate between normal cognition and cognitive impairment. In some cases, MCI can include cognitive impairment that meets the criteria for dementia but exceeds the degree of normal aging. MCI varies in clinical manifestations, causes, prognosis, and prevalence. In some cases, MCI can be a pathological stage of Alzheimer's disease. Some forms of cognitive impairment can be considered early manifestations of neurodegenerative diseases that will eventually lead to dementia. In this application, the terms "intermediate cognitive impairment" and "moderate cognitive impairment" are used interchangeably and can include more severe memory impairment that affects the patient's ability to live independently and / or may be accompanied by sphincter dysfunction. In this application, the terms "late cognitive impairment" and "severe cognitive impairment" are used interchangeably and can include severe intellectual impairment, inability to care for oneself, complete dependence on others for care, and / or significant sphincter dysfunction. The severity of cognitive impairment can be determined by clinical manifestations, impairment in daily functions, or cognitive assessments. For example, the severity of cognitive impairment can be diagnosed using the Activity of Daily Living Scale (ADL), the Clinical Dementia Rating (CDR), or the Global Deterioration Scale (GDS). As used herein, the term "normal aging-related cognitive impairment" generally refers to cognitive impairment due to normal aging. For example, normal aging-related cognitive impairment may manifest as memory loss, confusion about the location of familiar places, taking longer than usual to complete daily tasks, or changes in mood and personality. Throughout this application, the term "Lewy body dementia (LBD)" generally refers to Lewy body dementia. Lewy body dementia is characterized by abnormal buildup of proteins called Lewy bodies. Lewy body dementia causes a gradual decline in mental abilities. People with Lewy body dementia may experience visual hallucinations and changes in alertness and attention. Other effects include muscle stiffness, slowed movements, difficulty walking, and tremors. People with Lewy bodies in their brains can also have plaques and tangles associated with Alzheimer's disease. In this application, the term "frontotemporal dementia" generally refers to Pick's disease, a rare, progressive disorder in which the tau protein affects only the frontal and temporal lobes of the brain. People with frontotemporal dementia have difficulty with higher-level reasoning, expressive language, speech perception, and memory formation. Over time, the frontal and temporal lobes of the brain can shrink in people with frontotemporal dementia. As used herein, the term "vascular dementia" generally refers to problems with reasoning, judgment, and memory caused by impaired blood flow to the brain. For example, vascular dementia can include dementia caused by factors that increase the risk of heart disease and stroke, such as high blood pressure and high cholesterol. In this application, the term "multi-infarct type" generally refers to small, non-cortical infarcts caused by occlusion of a single perforating branch of a large cerebral artery. The multi-infarct type can be a special type of cerebral infarction, also known as ischemic stroke. The multi-infarct type can manifest as hemisensory disturbances, aphasia, dysarthria, slow movements, and clumsiness (particularly difficulty with fine motor skills such as handwriting). In this application, the term "Parkinson's disease" generally refers to a progressive neurodegenerative disease. The clinical features of Parkinson's disease (PD) can include motor symptoms (e.g., tremor, bradykinesia, muscle rigidity, and postural instability), as well as neuropsychiatric and other non-motor manifestations. For example, the non-motor manifestations can include cognitive dysfunction and dementia, mood disorders (e.g., depression, anxiety, apathy), and sleep disorders. In this application, the term "AIDS" generally refers to acquired immunodeficiency syndrome (AIDS). Clinical manifestations of AIDS include changes in memory, concentration, attention, and motor skills. In some cases, AIDS patients may develop cognitive impairment. For example, approximately 50% of infected individuals may further develop HIV-associated neurocognitive disorders (HAND). In this application, the term "CJD" generally refers to a transmissible spongiform encephalopathy that occurs in humans. CJD is caused by infection with a prion virus. CJD patients may experience paranoid behavior, confusion, loss of appetite and weight, depression, and, in a minority of cases, visual or auditory abnormalities. In advanced stages, symptoms include progressive neurological deterioration (e.g., paresthesias, speech disorders, and aphasia). As used herein, the term "multiple sclerosis (MS)" generally refers to a demyelinating neuropathy. In MS patients, the insulating material (i.e., myelin sheath) on the surface of nerve cells in the brain or spinal cord is damaged, impairing signal transduction in the nervous system. This can lead to a range of symptoms that can affect the patient's mobility, mental state, and even mental state. These symptoms can include double vision, unilateral vision loss, muscle weakness, sensory impairment, or coordination problems. In this application, the term "amyotrophic lateral sclerosis (ALS)" generally refers to Lou Gehrig's disease (ALS), also known as motor neuron disease, a progressive and fatal neurodegenerative disease. A small number of ALS patients may develop frontotemporal dementia. Some ALS patients experience degeneration of their senses of hearing, vision, touch, smell, and taste, and a very small number of ALS patients may also develop dementia. In this application, the term "Huntington's disease (HD)" generally refers to a genetic disorder that causes brain cell death. As the disease progresses, patients with HD experience increasing incoordination and progressively worsening abilities, until movement becomes difficult and speech becomes impossible. Mental abilities often decline, often progressing to dementia. In this application, the term "senile stage" generally refers to the aging stage of a subject. For example, for humans, the aging stage may be over 60 years old, over 70 years old, or over 75 years old; for mice, the aging stage may be over 10 months old, for example, over 13 months old or over 18 months old. In some cases, the aging stage of the subject may have one or more symptoms of learning impairment, memory impairment, memory loss, and / or brain dysfunction. In this application, the term "stroke" or "stroke" generally refers to a condition caused by cell death due to blockage or bleeding of one or more blood vessels supplying blood to the brain, including stroke and damage caused by stroke. For example, stroke can be an acute cerebrovascular disease. In this application, "ischemic stroke" generally refers to a stroke caused by blockage of one or more blood vessels supplying blood to the brain. Ischemic stroke can be caused by thrombosis, embolism and / or hypotension. Thrombosis can be caused by atherosclerosis, aneurysm, vascular malformation, arteritis and / or vasospasm. Ischemic stroke includes cerebral infarction, which can include lacunar infarction, ischemic cerebral infarction and / or hemorrhagic infarction. The types of ischemic stroke can include, for example, embolic stroke, cardioembolic stroke, thrombotic stroke, large vessel stroke, lacunar infarction, artery-artery stroke and cryptic stroke. In this application, "hemorrhagic stroke" generally refers to a stroke caused by bleeding from one or more blood vessels supplying blood to the brain. Hemorrhagic stroke can include intraparenchymal hemorrhage, intraventricular hemorrhage and / or subarachnoid hemorrhage. Hemorrhagic stroke can include primary cerebral hemorrhage and / or secondary cerebral hemorrhage. Hemorrhagic stroke can include aneurysmal subarachnoid hemorrhage. Hemorrhagic stroke can be caused by vascular malformations, aneurysms, blood diseases, cerebral amyloid angiopathy, abnormal vascular network at the base of the brain, cerebral arteritis, anticoagulation or thrombolytic therapy and / or aneurysmal stroke. In the present application, the term "damage caused by stroke" generally refers to a condition caused directly or indirectly by a stroke. Damage caused by a stroke may include damage that occurs simultaneously with the stroke and damage caused after the stroke occurs. Damage caused by a stroke may include damage in the brain. The damage caused by a stroke may not be limited to the location where the stroke occurs, and may include damage to the entire body of the patient who has suffered a stroke, as long as it is related to the stroke or the occurrence of a stroke. The damage caused by a stroke may manifest as damage to the learning ability and / or behavioral ability of the patient who has suffered a stroke. The damage caused by a stroke may manifest as damage to the cognitive ability, motor ability and / or spatial exploration ability of the patient who has suffered a stroke. The damage caused by a stroke can be detected by known means, including but not limited to imaging observations, novel object recognition tests and water maze tests. In this application, the term "nanoparticle" generally refers to a microscopic particle having at least one dimension less than 100 nm. Typically, nanoparticles have a diameter in the range of 50 nm to 500 nm (i.e., 0.05 μm to 0.5 μm); are structurally stable in physiological environments; and are capable of accommodating smaller molecules (such as molecules that bind to ATP6V1B2 and / or functionally active fragments thereof), which can then be delivered to the desired site. The nanoparticles described herein include particles of different structures, such as nanospheres and nanocapsules. In this application, the nanoparticles include liposomes. In this application, the term "liposome" generally refers to a vesicle with an internal space that is separated from the external medium by one or more bilayer membranes. For example, the bilayer membrane can be formed by amphiphilic molecules, such as synthetic or naturally derived lipids containing spatially separated hydrophilic and hydrophobic domains; for another example, the bilayer membrane can be formed by amphiphilic polymers and surfactants. The internal space of the liposome can be loaded with hydrophilic drugs, while the space between its bilayer membranes can be loaded with lipophilic drugs. For example, the liposomes described in this application can be used to load molecules that bind to ATP6V1B2 and / or its functionally active fragments as described in this application, thereby delivering the molecules to the desired site. In some cases, in order to better achieve the purpose of liposome delivery of molecules, improve delivery efficiency or delivery targeting, the liposomes can be further modified. For example, the modifications can include polypeptide modifications, antibody modifications, glycosyl modifications, ligand modifications, nucleic acid aptamers and / or multi-targeting modifications. In this application, the term "subject" generally refers to a human or non-human animal, including but not limited to a cat, dog, horse, pig, cow, sheep, rabbit, mouse, rat, or monkey. In this application, the term "comprising" generally means including, encompassing, containing or encompassing. In some cases, it also means "being", "consisting of...". In this application, the term "about" generally refers to a numerical range that is 20% more or less than a specific value. For example, "about X" includes a numerical range of ±20%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2% or ±0.1% of X, where X is a numerical value. Detailed Description of the Invention ATP6V1B2 and its functionally active fragments In the present application, the ATP6V1B2 may be derived from any organism. For example, the ATP6V1B2 may be derived from humans or mice. In the present application, the ATP6V1B2 may comprise the amino acid sequence shown in SEQ ID NO. 8 or 16. In the present application, the functionally active fragment of ATP6V1B2 may have the ability to specifically bind to the amino acid sequence set forth in SEQ ID NO. 5. For example, the functionally active fragment of ATP6V1B2 may comprise a truncated form of ATP6V1B2. For example, the functionally active fragment of ATP6V1B2 may comprise at least a portion of the amino acid sequence from positions 287 to 512 of the human ATP6V1B2 protein. For example, the functionally active fragment of ATP6V1B2 may comprise at least a portion of the amino acid sequence from positions 287 to 512 of the mouse ATP6V1B2 protein. In the present application, the ATP6V1B2 and / or its functionally active fragment may comprise the amino acid sequence shown in any one of SEQ ID NOs: 8, 10-11, and 16. In the present application, the nucleic acid sequence encoding the ATP6V1B2 and / or its functionally active fragment may include the nucleic acid sequence shown in SEQ ID NO: 9 or 17. In the present application, the activity of ATP6V1B2 can include the biological activity of ATP6V1B2 protein and / or its functionally active fragment (e.g., can include a measurable downstream effect caused by it). For example, the activity of ATP6V1B2 can include increasing the expression level and / or activity of the proton pump-related protein. In the present application, the increase can include increasing the activity of the proton pump-related protein by at least about 10% compared to the activity of the original proton pump-related protein in the subject. For example, it can increase by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. binder In one aspect, the present application provides a binding agent comprising a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof. In the present application, the binding of the binding agent or the molecule capable of binding to ATP6V1B2 and / or its functionally active fragment to ATP6V1B2 may be specific. For example, the binding agent or the molecule capable of binding to ATP6V1B2 and / or its functionally active fragment may be greater than or equal to about 10 5 M -1 (For example, greater than or equal to about 10 5 M -1 , greater than or equal to about 10 6 M - 1 , greater than or equal to about 10 7 M -1 , greater than or equal to about 10 8 M -1 , greater than or equal to about 10 9 M -1 , greater than or equal to about 10 10 M - 1 , greater than or equal to about 10 11 M-1, greater than or equal to about 10 12 M -1 , greater than or equal to about 10 13 M -1 or greater) of Ka (i.e., the equilibrium association constant for the binding interaction, which is 1 / M); or, -5 M (e.g., less than or equal to about 10 -5 M, less than or equal to about 10 -6 M, less than or equal to about 10 -7 M, less than or equal to about 10 -8 M, less than or equal to about 10 -9 M, less than or equal to about 10 -10 M, less than or equal to about 10 -11 M, less than or equal to about 10 -12 M, less than or equal to about 10 -13 The binding agent or the molecule capable of binding to ATP6V1B2 and / or its functionally active fragment binds or associates with ATP6V1B2 with an equilibrium dissociation constant Kd of 4 M or less. For example, the binding of the binding agent or the molecule capable of binding to ATP6V1B2 and / or its functionally active fragment can be in vivo or in vitro. In the present application, the binding agent may include a small molecule compound, a polymer and / or a biomacromolecule. In the present application, the binding agent may include a protein and / or a polypeptide. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises at least one mutated amino acid residue compared to the amino acid sequence set forth in SEQ ID NO: 85. In certain embodiments, the number of mutated amino acid residues is 1 to 8. For example, the number of mutated amino acid residues is 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, the at least one mutated amino acid residue is at least two mutated amino acid residues. For example, the number of mutated amino acid residues is 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. For example, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises 1, 2, 3, 4, or 5 mutated amino acid residues compared to the amino acid sequence set forth in SEQ ID NO: 85. In certain embodiments, the mutation site of the at least one mutated amino acid residue is located at position 1, 2, 5, 6 and / or 8 of the amino acid sequence as shown in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 1 of the amino acid sequence set forth in SEQ ID NO: 85. For example, the amino acid mutation at position 1 can be to any amino acid. For example, the amino acid mutation at position 1 can be to arginine or threonine. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 2 of the amino acid sequence set forth in SEQ ID NO: 85. For example, the amino acid mutation at position 2 can be to any amino acid. For example, the amino acid mutation at position 2 can be to tryptophan or aspartic acid. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 5 of the amino acid sequence set forth in SEQ ID NO: 85. For example, the amino acid mutation at position 5 can be mutated to any amino acid. For example, the amino acid mutation at position 5 can be mutated to glycine, phenylalanine, or tyrosine. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 6 of the amino acid sequence set forth in SEQ ID NO: 85. For example, the amino acid mutation at position 6 can be to any amino acid. For example, the amino acid mutation at position 6 can be to threonine, phenylalanine, or tyrosine. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises a mutation at position 8 of the amino acid sequence set forth in SEQ ID NO: 85. For example, the amino acid mutation at position 8 can be mutated to any amino acid. For example, the amino acid at position 8 can be absent. For example, the amino acid mutation at position 6 can be mutated to asparagine. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises a mutated amino acid combination compared to the amino acid sequence shown in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 1 and / or an amino acid mutation at position 5 of the amino acid sequence as shown in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises a mutation of the amino acid at position 1 to arginine and / or a mutation of the amino acid at position 5 to glycine compared to the amino acid sequence as shown in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 2 and / or an amino acid mutation at position 6 of the amino acid sequence set forth in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises a mutation at position 2 to aspartic acid and / or a mutation at position 5 to phenylalanine compared to the amino acid sequence set forth in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 2, an amino acid mutation at position 5, and / or an amino acid mutation at position 6 of the amino acid sequence as shown in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 2 to aspartic acid, an amino acid mutation at position 5 to tyrosine, and / or an amino acid mutation at position 6 to tyrosine, compared to the amino acid sequence as shown in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 1, an amino acid mutation at position 2, an amino acid mutation at position 5, and / or an amino acid mutation at position 6 of the amino acid sequence as shown in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 2 to aspartic acid, an amino acid mutation at position 5 to tyrosine, and / or an amino acid mutation at position 6 to tyrosine, compared to the amino acid sequence as shown in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 2, an amino acid mutation at position 5, an amino acid mutation at position 6, and / or an amino acid mutation at position 8 of the amino acid sequence as set forth in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises, compared to the amino acid sequence as set forth in SEQ ID NO: 85, an amino acid mutation at position 2 to aspartic acid, an amino acid mutation at position 5 to phenylalanine, an amino acid mutation at position 6 to threonine, and / or an amino acid mutation at position 8 to asparagine. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises a mutation at amino acid position 1, a mutation at amino acid position 2, a mutation at amino acid position 5, and / or a mutation at amino acid position 6 of the amino acid sequence set forth in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises a mutation at amino acid position 1 to threonine, a mutation at amino acid position 2 to tryptophan, a mutation at amino acid position 5 to phenylalanine, and / or a mutation at amino acid position 6 to threonine, compared to the amino acid sequence set forth in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises a mutation at amino acid position 1 to arginine, a mutation at amino acid position 2 to tryptophan, a mutation at amino acid position 5 to phenylalanine, and / or a mutation at amino acid position 6 to tyrosine, compared to the amino acid sequence set forth in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid mutation at position 1, an amino acid mutation at position 2, an amino acid mutation at position 5, an amino acid mutation at position 6, and / or an amino acid mutation at position 8 of the amino acid sequence as set forth in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises, compared to the amino acid sequence as set forth in SEQ ID NO: 85, a mutation at position 1 to threonine, a mutation at position 2 to tryptophan, a mutation at position 5 to phenylalanine, a mutation at position 6 to threonine, and / or a mutation at position 8 to asparagine. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises the amino acid sequence of SEQ ID NO: 19 and / or a variant thereof, wherein X is any amino acid. The amino acid sequence represented by SEQ ID NO: 19 is: XXVDXXC[X-], where X is any amino acid, and amino acid position 8 may be absent. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid sequence shown in any one of SEQ ID NOs: 20-24 and / or a variant thereof, wherein X is any amino acid. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises the amino acid sequence of any one of SEQ ID NOs: 25-30 and / or variants thereof, wherein X is any amino acid. The amino acid sequence of SEQ ID NO: 26 is: XXVDXXC[-S], wherein X is any amino acid, and [-S] indicates that position 8 may be serine or absent. The amino acid sequence of SEQ ID NO: 28 is: XXVDXXCX, wherein X is any amino acid. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid sequence shown in any one of SEQ ID NOs: 31-35 and / or a variant thereof, wherein X is any amino acid. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises the amino acid sequence of any one of SEQ ID NOs: 36-41 and / or variants thereof, wherein X is any amino acid. The amino acid sequence of SEQ ID NO: 37 is: [RTS][PWD]VD[GFYV][VTY]C[-S], wherein position 1 can be arginine, threonine, or serine, position 2 can be proline, tryptophan, or aspartic acid, position 5 can be glycine, phenylalanine, tyrosine, or valine, position 6 can be valine, threonine, or tyrosine, and position 8 can be serine or absent. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof comprises an amino acid sequence shown in any one of SEQ ID NOs: 42-48 and / or a variant thereof, wherein X is any amino acid. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof does not comprise the amino acid sequence set forth in SEQ ID NO: 85. In certain embodiments, the amino acid sequence of the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof is not completely identical to the amino acid sequence set forth in SEQ ID NO: 85. In the present application, the variant may include an amino terminal deletion, a carboxyl terminal deletion, an internal deletion and / or an amino acid substitution, while the remaining amino acid sequence generally has the same amino acids as the corresponding positions of the amino acid sequence from which it is derived. In certain embodiments, the variant generally has at least 60%, 70%, 80%, 90%, or 100% of the biological activity of the amino acid sequence from which it is derived. In certain embodiments, the binding agent or molecule capable of binding to ATP6V1B2 and / or its functionally active fragment comprises a protein and / or a polypeptide. In the present application, the molecule capable of binding to ATP6V1B2 and / or its functionally active fragment can be a polypeptide, which can contain cysteine residues. The cysteine residues in the amino acid sequence of the polypeptide may not be modified to block sulfhydryl groups. For example, if the cysteine residues in the amino acid sequence of the polypeptide are blocked by sulfhydryl groups, the polypeptide may lose its ability to bind to the ATP6V1B2 protein. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof may be a polypeptide, which may contain a serine residue, and the serine residue in the amino acid sequence of the polypeptide is not phosphorylated. For example, if the serine residue in the amino acid sequence of the polypeptide is phosphorylated, the polypeptide may lose the ability to bind to the ATP6V1B2 protein. In certain embodiments, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof may be a multimer. For example, the multimer may include a homodimer. In certain embodiments, the binding agent may comprise a single molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof as a first portion. In certain embodiments, the binding agent may optionally further comprise a second portion. In certain embodiments, the binding agent or molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof can be a fusion protein and / or fusion polypeptide. For example, the fusion protein and / or fusion polypeptide can include a first portion and a second portion. For example, the fusion protein and / or polypeptide can include a binding agent for ATP6V1B2 described herein and / or a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof described herein as a first portion. For example, the fusion protein and / or polypeptide can include a portion that is identical, different, or not identical to the first portion as a second portion. In certain embodiments, the first portion and the second portion are directly or indirectly connected. For example, the first portion and the second portion can be connected by a peptide bond. For example, the first portion and the second portion can be connected by a linker. For example, the first portion and the second portion can be connected by a non-peptide bond. In certain embodiments, the second portion may have a specific function. For example, the second portion may be capable of transporting across the blood-brain barrier to the brain. For example, the second portion may comprise a molecule capable of transporting across the blood-brain barrier to the brain. For example, the molecule capable of transporting across the blood-brain barrier to the brain comprises a polypeptide. For example, the second portion may comprise a cell-penetrating peptide. For example, the cell-penetrating peptide is capable of transporting across the blood-brain barrier to the brain. For example, the second portion comprises the amino acid sequence set forth in any one of SEQ ID NOs: 79-84. In certain embodiments, the fusion protein and / or polypeptide may include a binder to ATP6V1B2 as described herein and / or a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof as described herein as a first portion, and a cell-penetrating peptide as a second portion. For example, the molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof and the cell-penetrating peptide may be linked by a peptide bond to form a fusion polypeptide and / or fusion protein. In certain embodiments, the binding agent comprises an amino acid sequence as shown in any one of SEQ ID NOs: 49-71 and / or a variant thereof, wherein X is any amino acid. In certain embodiments, the binding agent comprises an amino acid sequence as shown in any one of SEQ ID NOs: 72-78 and / or a variant thereof. On the other hand, the present application provides a binding agent, which may comprise two parts, the first part comprising a molecule that binds to ATP6V1B2 and / or a functionally active fragment thereof, and the second part comprising a molecule that delivers the first part. In certain embodiments, the binding agent consists of the first part and the second part. In certain embodiments, the binding agent comprises at least the first part and the second part. In the present application, the form of the second part is not limited, and all forms of molecules that can achieve delivery of the first part are included. In certain embodiments, the second part can include a modifying group, a small molecule, a nanoparticle, an exosome, a virus, a nucleic acid, a protein and / or a polypeptide. In the present application, the second part has the function of delivering the first part into cells and / or transporting the first part across the blood-brain barrier to the brain. In certain embodiments, the second part is capable of delivering the first part into cells expressing ATP6V1B2. In the present application, the second portion includes a modification or transformation of the molecule of the first portion so that it can be delivered to a location where it can function. For example, the second portion may include a group that is rationally designed and modified to modify the molecule of the first portion, changing its properties to make it easier to cross the blood-brain barrier and / or enter cells. In certain embodiments, the second portion may include a group for modifying the first portion. In certain embodiments, the second portion may include a group for PEGylation, lipidation, and / or glycosylation of the first portion. In the present application, the first part can be wrapped inside the second part so that it can be delivered to the position where it can play a role. In some embodiments, the second part can include nanoparticles. For example, the second part can include liposomes. In some embodiments, the nanoparticles and / or liposomes can be further modified or transformed to improve the delivery effect of the first part. In some embodiments, the second part can include liposomes, and the liposomes can include modified liposomes, and the modifications include polypeptide modification, antibody modification, glycosyl modification, ligand modification, nucleic acid aptamer and / or multi-target modification. In certain embodiments, the second portion may include a molecule that interferes with the physiological barrier function of the blood-brain barrier and / or a binder to a transporter protein on the blood-brain barrier. In certain embodiments, the interference with the physiological barrier function of the blood-brain barrier may include increasing the permeability of the blood-brain barrier. In certain embodiments, the interference with the physiological barrier function of the blood-brain barrier may include inhibiting the efflux system of the blood-brain barrier. In certain embodiments, the molecule that interferes with the physiological barrier function of the blood-brain barrier includes an efflux inhibitor. In some embodiments, the second part can include a binder for a transporter on the blood-brain barrier to complete the trans-blood-brain barrier delivery of the first part of the molecule by the transporter. In some embodiments, the transporter on the blood-brain barrier can include insulin receptor (IR), transferrin receptor (TfR), low density lipoprotein receptor (LDLR), low density lipoprotein receptor-related protein 1 (LRP1) and LRP2 and / or diphtheria toxin receptor (DTR). In certain embodiments, the binding agent for the transporter on the blood-brain barrier may include a transporter binding protein on the blood-brain barrier. In certain embodiments, the transporter binding protein on the blood-brain barrier may include an antibody and / or an antigen-binding fragment thereof that targets the transporter on the blood-brain barrier. In certain embodiments, the transporter binding protein on the blood-brain barrier may include an antibody and / or an antigen-binding fragment thereof that targets the transferrin receptor. In certain embodiments, the second portion includes a binding agent for a protein that mediates endocytosis, so as to directly or indirectly complete the intracellular delivery of the first portion of molecules via the protein that mediates endocytosis. In certain embodiments, the protein that mediates endocytosis may include a protein and / or polypeptide that directly participates in endocytosis, or may include a protein and / or polypeptide that indirectly participates in endocytosis, as long as the binding agent can deliver the first portion of molecules into the cell. In certain embodiments, the second portion may include a cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide may include a cell-penetrating peptide that enters the cell through an endocytic pathway and / or a direct penetration pathway. In certain embodiments, the cell-penetrating peptide may include: a cationic cell-penetrating peptide, an amphipathic cell-penetrating peptide and / or a hydrophobic cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide may include a linear peptide and / or a cyclic peptide. For example, the second portion may include a cell-penetrating peptide and / or a variant thereof selected from the following table: In some embodiments, the second portion may include a cell-penetrating peptide derived from TAT protein. In some embodiments, the second portion may include a variant of a cell-penetrating peptide derived from TAT protein, and the variant may include amino terminal deletion, carboxyl terminal deletion, internal deletion and / or amino acid replacement, and the remaining amino acid sequence generally has the same amino acid as the corresponding position of the amino acid sequence from which it is derived. In some embodiments, the variant generally has at least 60%, 70%, 80%, 90%, or 100% biological activity of the amino acid sequence from which it is derived. In some embodiments, the variant of the cell-penetrating peptide derived from TAT protein, has the function of delivering the first portion to intracellular and / or allowing it to be transported to the brain across the blood-brain barrier. In certain embodiments, the second portion may comprise the amino acid sequence shown in SEQ ID NO: 79 and / or variants thereof. In certain embodiments, the second portion may comprise an amino acid sequence having at least one amino acid deleted at the N-terminus compared to the amino acid sequence set forth in SEQ ID NO: 79. In certain embodiments, the second portion may comprise an amino acid sequence having one to five amino acid deleted at the N-terminus compared to the amino acid sequence set forth in SEQ ID NO: 79. In certain embodiments, the second portion may comprise an amino acid sequence having one, two, three, four, or five amino acid deleted at the N-terminus compared to the amino acid sequence set forth in SEQ ID NO: 79. In certain embodiments, the second portion may comprise the amino acid sequence shown in any one of SEQ ID NOs: 80-84 and / or variants thereof. In some embodiments, the second portion can be connected to the first portion. In some embodiments, the first portion and the second portion are directly or indirectly connected. In some embodiments, the first portion and the second portion can be connected by a peptide bond. In some embodiments, the first portion and the second portion can be connected by a linker. In some embodiments, the first portion and the second portion can be connected by a non-peptide. In certain embodiments, the first portion may comprise a molecule described herein that is capable of binding to ATP6V1B2 and / or a functionally active fragment thereof. In certain embodiments, the first portion may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 19-30, 93-99, and / or variants thereof, wherein X is any amino acid. In certain embodiments, the first portion may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 31-48, 86-92, and / or variants thereof. In certain embodiments, the first portion may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 85, and / or variants thereof. In certain embodiments, wherein the binding agent comprises a protein and / or a polypeptide. In certain embodiments, the first portion comprises a protein and / or a polypeptide. In certain embodiments, the first portion may be a polypeptide, which may contain cysteine residues. The cysteine residues in the amino acid sequence of the polypeptide may not be modified to block sulfhydryl groups. For example, if the cysteine residues in the amino acid sequence of the polypeptide are blocked by sulfhydryl groups, the polypeptide may lose its ability to bind to the ATP6V1B2 protein. In certain embodiments, the first portion may be a polypeptide, which may contain a serine residue, and the serine residue in the amino acid sequence of the polypeptide is not phosphorylated. For example, if the serine residue in the amino acid sequence of the polypeptide is phosphorylated, it may lose the ability to bind to the ATP6V1B2 protein. In certain embodiments, the first portion can be a multimer. In certain embodiments, the multimer can include a homodimer. In certain embodiments, the binding agent may be a fusion protein and / or fusion polypeptide. In certain embodiments, the fusion protein and / or fusion polypeptide may include the first portion and the second portion. In certain embodiments, the first portion includes a molecule that binds to ATP6V1B2 and / or a functionally active fragment thereof, the second portion includes a molecule that delivers the first portion, and the first portion and the second portion form a fusion polypeptide. In certain embodiments, the binding agent comprises the amino acid sequence set forth in any one of SEQ ID NOs: 100-104 and / or variants thereof. In certain embodiments, the binding agent may comprise the amino acid sequence set forth in SEQ ID NO: 1 and / or variants thereof. In certain embodiments, the binding agent may comprise the amino acid sequence set forth in SEQ ID NO: 5 and / or variants thereof. Function of the binder In the present application, the binding agent can regulate the expression level and / or activity of a proton pump-related protein. For example, the binding agent can increase the expression level and / or activity of a proton pump-related protein. For example, the expression level of the proton pump-related protein includes the expression level of a gene encoding a proton pump-related protein, the transcription level of a gene encoding a proton pump-related protein, and / or the expression level of a proton pump-related protein. For example, the increase includes increasing the expression level and / or activity of the proton pump-related protein by at least about 10% compared to the expression level and / or activity of the original proton pump-related protein in the subject. In the present application, the increase may include increasing the expression level of the proton pump-related protein by at least about 10% compared to the expression level of the original proton pump-related protein in the subject. For example, the improvement can be at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500%, or more. For example, the expression level of a proton pump-related protein can be measured by conventional techniques in the art. For example, including but not limited to measuring the expression level of a proton pump-related protein by performing an assay selected from the group consisting of: qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. For example, the expression level of a proton pump-related protein can be measured, but not limited to, by utilizing a substance selected from the group consisting of: a primer capable of specifically amplifying a gene encoding a proton pump-related protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-related protein, a nucleic acid molecule that specifically binds to a proton pump-related protein, a small molecule that specifically binds to a proton pump-related protein, a probe that specifically binds to a proton pump-related protein, and a polypeptide that specifically binds to a proton pump-related protein. In the present application, the proton pump-related protein may include NADH dehydrogenase, coenzyme Q, succinate-Coenzyme Q reductase, cytochrome c and / or coenzyme Q-cytochrome c reductase. In the present application, the activity of the proton pump-associated protein may include the biological activity of the proton pump-associated protein. For example, the activity of the proton pump-related protein can be measured by the activity level of the hydrogen / potassium ATPase system (also known as hydrogen / potassium ion ATPase, i.e., H+ / K+ATPase); and / or the activity level of the H2 receptor. For example, the activity of the proton pump-related protein can be measured by its ability to regulate lysosomal acidity. For example, the activity of the proton pump-related protein can be measured by the acidity level of the lysosome. Lysosomal acidity generally refers to the acidic environment inside the lysosome (lysosome) in the cell, which is usually maintained by the proton pump (H+-ATPase) on the lysosomal membrane. The main function of the lysosomal H+-ATPase is to transport protons on the negative side of the cell to the lysosomal chamber, thereby maintaining or increasing the acidic environment of the lysosome. ATP6V1B2 participates in the formation of the proton pump, can regulate the activity of the proton pump, and can directly affect the proton (H+ ion) concentration in the lysosome. In the present application, the increase in the activity of the proton pump-associated protein can include an increase in the activity of the proton pump-associated protein by at least about 10% compared to the activity of the original proton pump-associated protein in the subject. For example, the activity can be increased by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the binding agent can modulate the expression level and / or biological activity of ATP6V1B2 and / or a functionally active fragment thereof. For example, the binding agent can increase the expression level and / or biological activity of ATP6V1B2. In the present application, the increase can include increasing the expression level of ATP6V1B2 by at least about 10% compared to the original expression level of ATP6V1B2 in the subject. For example, the increase can be at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500%, or more. For example, the expression level of ATP6V1B2 includes the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein. For example, the expression level can include the amount of a specific gene (e.g., human ATP6V1B2 gene) polynucleotide, mRNA, or amino acid product or protein. The expression level can include the amount of a specific gene (e.g., human ATP6V1B2 gene) transcribed polynucleotide, translated protein, or post-translationally modified protein fragment. For example, the expression level of ATP6V1B2 can be measured by conventional techniques in the art. For example, this includes, but is not limited to, measuring the expression level of ATP6V1B2 by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. For example, the expression level of ATP6V1B2 can be measured, but is not limited to, using a substance selected from the group consisting of: a primer that specifically amplifies the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 protein, a small molecule that specifically binds to the ATP6V1B2 protein, a probe that specifically binds to the ATP6V1B2 protein, and a polypeptide that specifically binds to the ATP6V1B2 protein. In the present application, the binding agent can improve cognitive ability. For example, the cognitive ability can include cognitive ability that can be measured by a novel object recognition behavioral experiment. For example, the cognitive ability can include cognitive ability that can be measured by a water maze behavioral experiment. For example, the improvement can include that after the binding agent is administered to the subject, the subject's cognitive ability is improved. For example, the improvement in the subject's cognitive ability can include that in a water maze behavioral experiment, the subject's time in the quadrant where the platform is located is increased, the interval time to enter the quadrant where the platform is located is reduced, and / or the number of times the subject crosses the quadrant where the platform is located is increased. In the present application, the binding agent can increase neuronal synaptic transmitter release. For example, the increase includes an increase of at least about 10% compared to the level of original neuronal synaptic transmitter release in the subject. For example, it can increase by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the binding agent is capable of increasing the firing frequency of excitatory postsynaptic currents. In the present application, the increase includes an increase of at least about 10% compared to the level of the original firing frequency of excitatory postsynaptic currents in the subject. For example, the increase may be at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500%, or more. In the present application, the binding agent can regulate lysosomal acidity and / or affect the ability to regulate lysosomal acidity. For example, the binding agent can increase lysosomal acidity. For example, the increase in lysosomal acidity can include an increase in the concentration of H+ ions in the lysosome. In the present application, the increase can include an increase of at least about 10% compared to the original proton concentration in the lysosome in the subject. For example, it can increase by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. For example, lysosomal acidity can be detected by a pH-sensitive fluorescent probe. In the present application, the binding agent can improve learning ability, treat cognitive impairment, prevent and / or treat neurodegenerative diseases, and / or prevent and / or treat stroke. In the present application, the binding agent can prevent and / or treat diseases associated with lysosomes. For example, the diseases associated with lysosomes can include diseases associated with lysosomal abnormalities. For example, the diseases associated with lysosomes can include diseases associated with abnormal lysosomal acidity. Isolated peptides In another aspect, the present application provides isolated polypeptides. In certain embodiments, the polypeptide may comprise a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof as described herein and / or a binding agent as described herein. In certain embodiments, the polypeptide may comprise the amino acid sequence shown in SEQ ID NO: 19 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the polypeptide may comprise the amino acid sequence shown in any one of SEQ ID NOs: 20-24 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the polypeptide may comprise an amino acid sequence shown in any one of SEQ ID NOs: 25-30 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the polypeptide may comprise the amino acid sequence shown in any one of SEQ ID NOs: 31-35 and / or variants thereof. In certain embodiments, the polypeptide may comprise the amino acid sequence shown in any one of SEQ ID NOs: 36-41 and / or variants thereof. In certain embodiments, the polypeptide may comprise the amino acid sequence shown in any one of SEQ ID NOs: 42-48 and / or variants thereof. In the present application, the polypeptide may include a multimer. For example, the multimer may include a dimer. For example, the multimer may include a homodimer. In the present application, the cysteine residues in the amino acid sequence of the polypeptide may not be modified to block sulfhydryl groups. For example, if the cysteine residues in the amino acid sequence of the polypeptide are blocked by sulfhydryl groups, they may lose the ability to bind to the ATP6V1B2 protein. In the present application, the serine residue in the amino acid sequence of the polypeptide does not have a phosphorylation modification. For example, if the serine residue in the amino acid sequence of the polypeptide is phosphorylated, it may lose the ability to bind to the ATP6V1B2 protein. In the present application, the isolated polypeptide can be used as a binder for ATP6V1B2. In the present application, the isolated polypeptide can be used to prepare a binder for ATP6V1B2. In the present application, the isolated polypeptide can have one or more functions of an ATP6V1B2 binder. For example, the polypeptide can regulate the expression level and / or activity of a proton pump-related protein. For example, the polypeptide can regulate the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the polypeptide can increase the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the polypeptide can improve cognitive ability. For example, the polypeptide can increase neuronal synaptic transmitter release. For example, the polypeptide can increase the frequency of excitatory postsynaptic currents. For example, the polypeptide can improve learning ability, treat cognitive impairment, prevent and / or treat neurodegenerative diseases, and / or prevent and / or treat stroke. For example, the polypeptide can prevent and / or treat lysosome-related diseases. For example, the lysosome-related disease may include a disease associated with lysosome abnormality. For example, the lysosome-related disease may include a disease associated with abnormal lysosomal acidity. Fusion protein / fusion peptide In another aspect, the present application provides fusion proteins and / or fusion polypeptides. In the present application, the fusion protein and / or fusion polypeptide may comprise the molecule capable of binding to ATP6V1B2 and / or its functionally active fragment as described in the present application, the binding agent as described in the present application and / or the polypeptide as described in the present application. In certain embodiments, the fusion protein and / or fusion polypeptide may include a first portion and a second portion. For example, the fusion protein and / or polypeptide may include, as the first portion, a binder to ATP6V1B2, a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof, and / or a polypeptide as described herein. For example, the fusion protein and / or polypeptide may include, as the second portion, a portion that is identical, different, or not identical to the first portion. In certain embodiments, the first portion and the second portion are directly or indirectly connected. For example, the first portion and the second portion can be connected by a peptide bond. For example, the first portion and the second portion can be connected by a linker. For example, the first portion and the second portion can be connected by a non-peptide bond. In certain embodiments, the second portion may have a specific function. For example, the second portion may be transported across the blood-brain barrier to the brain and / or cross the cell membrane. In certain embodiments, the fusion protein and / or fusion polypeptide further comprises a molecule capable of being transported across the blood-brain barrier to the brain and / or a molecule capable of crossing the cell membrane. In certain embodiments, the molecule capable of being transported across the blood-brain barrier to the brain and / or a molecule capable of crossing the cell membrane comprises a polypeptide. In certain embodiments, the molecule capable of being transported across the blood-brain barrier to the brain and / or a molecule capable of crossing the cell membrane comprises a cell-penetrating peptide. In certain embodiments, the cell-penetrating peptide comprises an amino acid sequence as shown in any one of SEQ ID NOs: 79-84 or a variant thereof. In certain embodiments, the first portion and the second portion may be linked by a peptide bond to form a fusion polypeptide and / or fusion protein. For example, the second portion may bind to ATP6V1B2. For example, the second portion may bind completely, partially, or not at all to ATP6V1B2. For example, the second portion may affect the binding of the first portion to ATP6V1B2. For example, the second portion may enhance the binding of the first portion to ATP6V1B2. For example, a fusion polypeptide or protein comprising the first portion and the second portion may bind to ATP6V1B2 more strongly than the binding of the first portion to ATP6V1B2. For example, a fusion polypeptide or protein comprising the first portion and the second portion may bind to ATP6V1B2 more strongly than the binding of the first portion to ATP6V1B2 by at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, or more. For example, the second portion can weaken the binding ability of the first portion to ATP6V1B2. For example, the binding ability of a fusion polypeptide or protein comprising the first and second portions to ATP6V1B2 is weaker than the binding ability of the first portion to ATP6V1B2. For example, the binding ability of a fusion polypeptide or protein comprising the first and second portions to ATP6V1B2 is at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, or more weaker than the binding ability of the first portion to ATP6V1B2. For example, the binding ability can be measured using techniques commonly used in the art. For example, the binding ability can be represented by the equilibrium dissociation constant, Kd. For example, the binding ability can be determined by co-immunoprecipitation. In certain embodiments, the polypeptide may comprise the amino acid sequence shown in SEQ ID NO: 1 and / or a variant thereof. In certain embodiments, the polypeptide may comprise the amino acid sequence shown in SEQ ID NO: 5 and / or a variant thereof. In certain embodiments, the fusion protein and / or polypeptide may comprise an amino acid sequence as shown in any one of SEQ ID NOs: 49-71 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the fusion protein and / or polypeptide may comprise an amino acid sequence as shown in any one of SEQ ID NOs: 72-78 and / or variants thereof. In certain embodiments, the fusion protein and / or polypeptide may include a binding agent for ATP6V1B2 as described herein, a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof as described herein, and / or a polypeptide as described herein as a first portion and a molecule that delivers the first portion as a second portion. In certain embodiments, the binding agent described herein may be a fusion protein and / or polypeptide, the binding agent consisting of two portions, the first portion including a molecule that binds to ATP6V1B2 and / or a functionally active fragment thereof, and the second portion including a molecule that delivers the first portion. In the present application, the fusion protein and / or fusion polypeptide may have one or more functions of an ATP6V1B2 binder. For example, the fusion protein and / or fusion polypeptide may regulate the expression level and / or activity of a proton pump-related protein. For example, the fusion protein and / or fusion polypeptide may regulate the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the fusion protein and / or fusion polypeptide may increase the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the fusion protein and / or fusion polypeptide may improve cognitive ability. For example, the fusion protein and / or fusion polypeptide may increase neuronal synaptic transmitter release. For example, the fusion protein and / or fusion polypeptide may increase the frequency of excitatory postsynaptic currents. For example, the fusion protein and / or fusion polypeptide may improve learning ability, treat cognitive impairment, prevent and / or treat neurodegenerative diseases, and / or prevent and / or treat stroke. For example, the fusion polypeptide may prevent and / or treat lysosome-related diseases. For example, the lysosome-related disease may include a disease associated with lysosome abnormality. For example, the lysosome-related disease may include a disease associated with abnormal lysosomal acidity. Immunoconjugates In another aspect, the present application provides an immunoconjugate comprising the binding agent described herein, the polypeptide described herein, and / or the fusion polypeptide described herein. For example, the immunoconjugate can include one, two or more binding agents, polypeptides and / or polypeptides described herein. The immunoconjugates described herein have biological activity. For example, the biological activity may include the ability to bind ATP6V1B2 and / or its functionally active fragments in vivo or in vitro and elicit a reaction. For example, the reaction includes, but is not limited to, increasing the expression level and / or biological activity of ATP6V1B2 and / or its functional fragments, improving learning ability, treating cognitive impairment and / or treating neurodegenerative diseases. For example, the immunoconjugates can prevent and / or treat diseases associated with lysosomes. For example, the diseases associated with lysosomes may include diseases associated with lysosomal abnormalities. For example, the diseases associated with lysosomes may include diseases associated with abnormal lysosomal acidity. Nucleic acid molecules, vectors, cells The present application provides one or more nucleic acid molecules that can encode the binding agents, polypeptides, fusion polypeptides, and / or immunoconjugates described herein. For example, each of the one or more nucleic acid molecules can encode the entire binding agent, polypeptide, fusion polypeptide, or immunoconjugate, or a portion thereof. The nucleic acid molecules described herein can be isolated. For example, they can be produced or synthesized by the following methods: (i) in vitro amplification, such as by polymerase chain reaction (PCR) amplification, (ii) by cloning and recombination, (iii) purification, such as by enzyme digestion and gel electrophoresis fractionation, or (iv) synthesis, such as by chemical synthesis. In some embodiments, the isolated nucleic acid is a nucleic acid molecule prepared by recombinant DNA technology. Recombinant DNA and molecular cloning techniques include those described in Sambrook, J., Fritsch, EF and Maniatis, T. Molecular Cloning: A Laboratory Manual; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, (1989) (Maniatis) and in TJ Silhavy, ML Bennan and LV Enquist, Experiments with Gene Fusions, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1984) and in Ausubel, FM et al., Current Protocols in Molecular Biology, pub. by Greene Publishing Assoc. and Wiley-Interscience (1987). Briefly, the nucleic acids can be prepared from genomic DNA fragments, cDNA and RNA, all of which can be extracted directly from cells or recombinantly produced by various amplification methods, including but not limited to PCR and RT-PCR. In another aspect, the present application provides one or more vectors comprising the nucleic acid molecules. For example, the vector may comprise one or more nucleic acid molecules. In addition, the vector may further comprise other genes, such as marker genes that allow the vector to be selected in an appropriate host cell and under appropriate conditions. In addition, the vector may further comprise expression control elements that allow the coding region to be correctly expressed in an appropriate host. Such control elements are well known to those skilled in the art and may include, for example, promoters, ribosome binding sites, enhancers, and other control elements that regulate gene transcription or mRNA translation. The one or more nucleic acid molecules described herein may be operably linked to the expression control elements. The vector may include, for example, a plasmid, a cosmid, a virus, a phage or other vectors commonly used in, for example, genetic engineering. For example, the vector is an expression vector. On the other hand, the present application provides a cell, which may contain one or more binding agents described herein, one or more polypeptides described herein, one or more fusion polypeptides described herein, one or more nucleic acid molecules described herein, and / or one or more vectors described herein. In certain embodiments, each or each host cell may contain one or more nucleic acid molecules or vectors described herein. In certain embodiments, each or each host cell may contain multiple (e.g., 2 or more) or multiple (e.g., 2 or more) nucleic acid molecules or vectors described herein. The vectors described herein can be introduced into the cells by methods known in the art, such as electroporation, lipofection, and the like. Pharmaceutical composition On the other hand, the present application provides a pharmaceutical composition, which may include the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein, and optionally a pharmaceutically acceptable carrier. For example, the pharmaceutical composition can include a pharmaceutical product suitable for pharmaceutical uses (e.g., improving learning ability, treating cognitive impairment and / or treating neurodegenerative diseases (e.g., Alzheimer's disease)). For example, the pharmaceutical composition can be used to prevent and / or treat neurodegenerative diseases and / or prevent and / or treat stroke. For example, the pharmaceutical composition can be used to prevent and / or treat a disease associated with a lysosome. For example, the disease associated with a lysosome can include a disease associated with a lysosomal abnormality. For example, the disease associated with a lysosome can include a disease associated with an abnormal lysosomal acidity. For example, the pharmaceutical composition can be a composition comprising one or more active ingredients (such as the binding agents described herein) and one or more inert ingredients; as well as any product directly or indirectly obtained by the combination, complex or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. For example, the pharmaceutically acceptable carrier may include sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles may include water, ethanol, polyols (e.g., propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters such as ethyl oleate. Reagent test kit On the other hand, the present application provides a kit comprising the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein; and one or more additional components selected from the following group: analytical buffer, controls, substrates, standards, detection materials, laboratory supplies, equipment, instruments, cells, organs, tissues and user manuals or instructions. In the present application, the kit can detect ATP6V1B2 in a sample. For example, the kit can detect the expression level and / or biological activity of ATP6V1B2 and / or its functional fragments. For example, the kit can include instructions describing specific steps for using the kit to detect the expression level and / or biological activity of ATP6V1B2 and / or its functional fragments, and / or specific steps for using the test results to determine whether the candidate drug can prevent and / or treat cognitive impairment and / or neurodegenerative disease in a subject. Learning ability In the present application, when the expression level and / or activity of ATP6V1B2 in the subject is increased, the learning ability of the subject can be significantly improved (for example, the cognitive ability, motor ability, memory ability and / or spatial exploration ability can be significantly improved compared to before the expression level and / or activity of ATP6V1B2 in the subject is increased). Therefore, ATP6V1B2 can be used as a potential target for improving learning ability. For example, ATP6V1B2 can be used as a potential target for treating neurodegenerative diseases (such as Alzheimer's disease) and / or cognitive disorders. In this application, the learning ability may include all abilities related to or required for the learning / cognitive process. For example, the learning ability may include cognitive ability, motor ability, memory ability and / or spatial exploration ability. In the present application, the improvement of the learning ability can include that the assessment score of the learning ability of the experimenter after the improvement is improved by at least about 50% compared with the assessment score of the original learning ability of the experimenter.For example, it can be improved by at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the assessment score of the learning ability can be obtained by conducting an assessment including attention / executive function (e.g., Wechsler Memory Test), a language ability assessment (e.g., the language screening test (LAST)), a visual-spatial and structural ability assessment (e.g., a visual-motor integration test, a Hooper visual organization test, an object assembly test, a graphic arrangement test, a clock drawing test), an application ability assessment, an everyday function assessment (e.g., a disability assessment for dementia (DAD)), and / or a neuropsychological scale. For example, the assessment score of the learning ability can be measured by implementing a test selected from the group consisting of a novel object recognition test and a water maze test. In the present application, the novel object recognition test can evaluate the cognitive ability, motor ability and / or spatial exploration ability. In the present application, the novel object recognition test can make a subject (such as a mouse) explore and learn a specific shape of object in a fixed container, and distinguish the new object that is different from the previous object shape in the fixed container after a few days according to the memory obtained by learning. If the time that mice distinguish the new object of the different shape after a few days is shorter, then the learning ability of mice is correspondingly higher. The water maze evaluation test can be an important experiment for evaluating the learning ability of a subject. In the present application, the water maze test can evaluate the memory ability, motor ability and / or spatial exploration ability. In the present application, the water maze test (for example Morris water maze) can force subjects (for example mice) to swim, thereby learning to find a platform hidden in the water, and then testing mice to spatial exploration ability and / or memory ability of spatial position and sense of direction. The water maze test also can include acquired training, exploratory training, alignment training or alignment exploratory training. If mice is shorter from entering the water to finding the time required for the platform, the distance moved during this period is shorter, and the learning ability of mice is correspondingly higher. The water maze evaluation test can be an important experiment for evaluating subject's learning ability. The present application provides the use of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in the preparation of a reagent that can improve learning ability. The present application provides uses of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in improving learning ability. The present application provides a method for improving learning ability, comprising administering to a subject in need thereof the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein. Prevent and / or treat disease The present application provides the use of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in the preparation of an agent for preventing and / or treating a disease. The present application provides a method for preventing and / or treating a disease, which comprises administering to a subject in need thereof the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein, the pharmaceutical composition described herein and / or the reagent for preventing and / or treating a disease described herein. The present application provides the use of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in preventing and / or treating diseases. For example, the disease may include cognitive impairment. For example, the disease may include neurodegenerative disease. The agents described herein can be administered in any manner. For example, the agents described herein can be administered orally and / or by injection. For example, the agents described herein can be formulated into a form suitable for their mode of use. For example, the agents described herein can be formulated into a form suitable for oral administration and / or by injection. The binding agents described herein, the polypeptides described herein, the fusion polypeptides described herein, the immunoconjugates described herein, the nucleic acid molecules described herein, the vectors described herein, the cells described herein, the pharmaceutical compositions described herein, and / or the reagents for preventing and / or treating diseases described herein can be administered in a therapeutically effective dose. For example, a therapeutically effective dose may include an amount that effectively prevents or improves the symptoms of one or more diseases or conditions or the development of the disease or condition when administered to a subject. For example, a therapeutically effective dose may include an amount of a binding compound sufficient to cause symptom improvement, such as an amount that treats, cures, prevents, or improves a related medical condition or increases the speed of treatment, cure, prevention, or improvement of such a condition. For example, when a single active ingredient is administered to an individual, a therapeutically effective dose refers only to that ingredient. For example, when administered in combination, a therapeutically effective dose refers to the combined amount of active ingredients that cause a therapeutic effect, whether in combination, administered sequentially, or administered simultaneously. In the present application, the prevention and / or treatment not only includes preventing and / or treating the disease, but also generally includes preventing the onset of the disease, slowing or reversing the progression of the disease, preventing or slowing the onset of one or more symptoms associated with the disease, reducing and / or alleviating one or more symptoms associated with the disease, reducing the severity and / or duration of the disease and / or any symptoms associated therewith and / or preventing further increase in the severity of the disease and / or any symptoms associated therewith, preventing, reducing or reversing any physiological damage caused by the disease, and generally any pharmacological effect that is beneficial to the patient being treated. For example, the binding agents described herein, the polypeptides described herein, the fusion polypeptides described herein, the immunoconjugates described herein, the nucleic acid molecules described herein, the vectors described herein, the cells described herein, the pharmaceutical compositions described herein and / or the reagents for preventing and / or treating the disease described herein do not need to achieve a complete cure or eradicate any symptoms or manifestations of the disease. As recognized in the relevant art, drugs used as therapeutic agents can reduce the severity of a given disease state, but do not need to eliminate every manifestation of the disease to be considered a useful therapeutic agent. Similarly, a prophylactically administered treatment does not need to be completely effective in preventing the onset of a condition to constitute a viable preventative agent. It is sufficient to simply reduce the effects of the disease in the subject (e.g., by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or to reduce the likelihood of the disease occurring or worsening. Detection of ATP6V1B2 The present application provides a method for detecting ATP6V1B2 in a sample, which comprises administering the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the pharmaceutical composition described herein and / or the kit described herein. The present application provides uses of the binding agents, polypeptides, fusion polypeptides, immunoconjugates, nucleic acid molecules, vectors, cells, pharmaceutical compositions, and / or kits described herein in preparing a kit. For example, the kit can be used to detect ATP6V1B2 in a sample. In the present application, ATP6V1B2 in a sample can be detected by detecting the binding of the binding agent, polypeptide, fusion polypeptide, immunoconjugate, nucleic acid molecule, vector, cell, pharmaceutical composition, and / or kit described herein to ATP6V1B2 during the preparation of the kit. For example, the detection can include direct detection. For example, the detection can include indirect detection. For example, detecting ATP6V1B2 in a sample as described herein may include detecting the presence of ATP6V1B2 in the sample. For example, detecting ATP6V1B2 in a sample as described herein may include detecting the amount of ATP6V1B2 in the sample. For example, the ATP6V1B2 may include ATP6V1B2 and / or a nucleic acid encoding ATP6V1B2. The detection of ATP6V1B2 in a sample as described herein may include contacting the sample with the binding agent, polypeptide, fusion polypeptide, immunoconjugate, nucleic acid molecule, vector, cell, pharmaceutical composition, and / or kit described herein. For example, the detection process may include forming a binding agent-ATP6V1B2 complex. For example, the binding agent-ATP6V1B2 complex may release ATP6V1B2 for detection and analysis, or the binding agent-ATP6V1B2 complex may be used directly for detection. For example, the methods provided herein may directly test a sample. For example, the methods provided herein may simply involve contacting a sample with a binding agent. For example, the methods provided herein may simply involve contacting a sample with a binding agent and detecting binding. For example, the methods provided herein may involve contacting a sample with a binding agent, removing non-specifically bound substances, and detecting binding. For example, the binding agents described herein, the polypeptides described herein, the fusion polypeptides described herein, the immunoconjugates described herein, the nucleic acid molecules described herein, the vectors described herein, the cells described herein, the pharmaceutical compositions described herein, and / or the kits described herein can be attached to a carrier. For example, the binding agent is directly or indirectly attached to a carrier such as a magnetic bead or resin, or a mixture thereof. For example, the binding agent can also be directly or indirectly attached to a solid surface or substrate. For example, the binding agent can also be attached to particles, such as beads or microspheres. For example, the binding agent can also be labeled with substances including, but not limited to, magnetic labels, fluorescent moieties, enzymes, chemiluminescent probes, metal particles, non-metallic colloidal particles, polymeric dye particles, pigment molecules, pigment particles, electrochemically active substances, semiconductor nanocrystals or other nanoparticles (including quantum dots or gold particles). Subjects and Indications In the present application, the neurodegenerative disease may include acute neurodegenerative diseases and chronic neurodegenerative diseases. For example, the neurodegenerative disease may include neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by affected CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication and / or neurodegenerative diseases caused by impaired cell motility. In the present application, the cognitive impairment may include mild cognitive impairment (MCI), moderate cognitive impairment and severe cognitive impairment. For example, the cognitive impairment may include cognitive impairment caused by normal aging, Lewis's body dementia (LBD), frontotemporal dementia and / or vascular dementia. For example, the inducing disease of the cognitive impairment may include Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). In the present application, the stroke may include ischemic stroke and / or hemorrhagic stroke. In the present application, the ischemic stroke may include cerebral infarction. For example, the cerebral infarction may include lacunar infarction, ischemic cerebral infarction and / or hemorrhagic infarction. In the present application, the ischemic stroke may be caused by factors including: thrombosis, embolism and / or hypotension. For example, the thrombosis may be caused by factors including: atherosclerosis, aneurysm, vascular malformation, arteritis and / or vasospasm. In the present application, the hemorrhagic stroke may include intracerebral hemorrhage, intraventricular hemorrhage and / or subarachnoid hemorrhage. For example, the hemorrhagic stroke may include primary cerebral hemorrhage and / or secondary cerebral hemorrhage. For example, the hemorrhagic stroke may include aneurysmal subarachnoid hemorrhage. For example, the hemorrhagic stroke may be caused by factors including: vascular malformation, aneurysm, blood disease, cerebral amyloid angiopathy, abnormal vascular network at the base of the brain, cerebral arteritis, anticoagulation or thrombolytic therapy and / or tumor stroke. In the present application, the stroke may also include damage caused by the stroke. For example, the damage may include damage observed by imaging. For example, the damage observed by imaging may include intracerebral hematoma, intraventricular hemorrhage and / or subarachnoid hemorrhage. For example, the damage observed by imaging may include edema, hematoma and / or space-occupying effect. For example, the damage observed by imaging may include dense artery sign, island band sign, blurred outline of lenticular nucleus or reduced density, occlusion of cerebral perforator arterioles, edema and / or space-occupying effect. In the present application, the imaging observation may include conventional imaging observation means in this area. For example, the imaging observation may include but is not limited to ultrasound, CT, cranial angiography (CTA), CT perfusion scan (CTP), nuclear magnetic resonance (MRI) and digital subtraction angiography (DSA). For example, the impairment may include an impairment in learning abilities, including cognitive abilities, motor abilities, memory abilities, and / or spatial exploration abilities. In this application, the learning ability may include all abilities related to or required for the learning / cognitive process. For example, the learning ability may include cognitive ability, motor ability, memory ability and / or spatial exploration ability. In the present application, the damage of described learning ability can comprise and compare with the assessment score of learning ability before the generation cerebral stroke of experimenter, and the assessment score of the learning ability of described experimenter after the damage caused by cerebral stroke improves and reduces about 10%.For example, can reduce at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the subject may include a mammal. For example, the subject may include a rodent and / or a primate, for example, the subject may include a human. In the present application, the subject may include a non-cognitive disorder patient and / or a non-neurodegenerative disease patient. For example, the subject may be a normal person and / or a healthy person. For example, the subject may have a need and / or desire to further improve their learning ability. In the present application, the subject may include a patient with a neurodegenerative disease. For example, the subject may include a patient with Alzheimer's disease. For example, the patient with Alzheimer's disease may be in the early, early, middle, or late stages of Alzheimer's disease. In the present application, the subject may include a patient with cognitive impairment. For example, the subject may have early cognitive impairment (MCI) (e.g., difficulty in losing short-term memory, expressing or understanding abstract things, mood or behavior volatility, difficulty in learning new things and following complex instructions, decreased judgment and / or basic self-care needs to be reminded by others), moderate cognitive impairment (e.g., confusion between long-term memory and reality memory, poor expression, behavioral personality changes or emotional instability and / or the need for others to assist in self-care) or severe cognitive impairment (e.g., memory impairment, physical activity and mental state decline, cannot be effectively expressed or communicated, cannot take care of oneself and / or biological clock confusion). In the present application, the subject may have a disease that can cause the cognitive impairment to be induced. For example, the subject may have Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). In the present application, the subject may be elderly. For example, the subject may have exhibited cognitive impairment due to normal aging. For example, the subject may have exhibited symptoms of early cognitive impairment (MCI). For example, the subject may have exhibited symptoms of a neurodegenerative disease (e.g., Alzheimer's disease). In the present application, the subject may include a stroke patient and / or a patient with damage caused by a stroke. For example, the subject may include a patient with ischemic stroke and / or hemorrhagic stroke. For example, the subject may include a patient with cerebral infarction. For example, the patient may include a patient with lacunar infarction, ischemic infarction and / or hemorrhagic infarction. For example, the patient may include a patient with thrombosis, embolism and / or hypotension. For example, the patient may include a patient with atherosclerosis, aneurysm, vascular malformation, arteritis and / or vasospasm. In the present application, the subject may include patients with intracerebral hemorrhage, intraventricular hemorrhage and / or subarachnoid hemorrhage. For example, the subject may include patients with primary cerebral hemorrhage and / or secondary cerebral hemorrhage. For example, the subject may include patients with aneurysmal subarachnoid hemorrhage. For example, the patient may include patients with vascular malformations, aneurysms, hematological diseases, cerebral amyloid angiopathy, abnormal vascular network at the base of the brain, cerebral arteritis, anticoagulation or thrombolytic therapy and / or tumor stroke. In the present application, the subject may also include patients with damage caused by stroke. For example, the patient may include patients with observed intracerebral hematoma, intraventricular hemorrhage and / or subarachnoid hemorrhage. For example, the patient may include patients with observed edema, hematoma and / or mass effect. For example, the patient may include patients with observed dense artery sign, island band sign, blurred outline or decreased density of the lenticular nucleus, occlusion of cerebral perforator arterioles, edema and / or mass effect. Without intending to be bound by any theory, the following examples are merely intended to illustrate the fusion protein, preparation method, and use of the present application, and are not intended to limit the scope of the present invention. Example Example 1 Binding of ATP6V1B2 Binding Agents to ATP6V1B2 Protein This example demonstrates that the ATP6V1B2 binder described in this application can bind to the ATP6V1B2 protein through immunoprecipitation experiments with the ATP6V1B2 binder and the ATP6V1B2 protein. An hATP6V1B2-myc expression plasmid was constructed and transfected into HEK 293 cells. Cell protein was extracted 48 hours after transfection using Pierce RIPA Lysis Buffer. For cells grown in a 60 mm dish, 500 μL of Pierce RIPA Lysis Buffer containing protease inhibitors was added. Cells were harvested using a cell scraper and transferred to a clean 1.5 mL EP tube. After mixing on a rotary mixer at 4°C for 1 hour, the cells were centrifuged at 13,000 rpm for 10 minutes at 4°C to remove cellular debris. hATP6V1B2 was aliquoted into seven aliquots. Six aliquots were spiked with QD202-biotin, GS18-biotin, RS17-biotin, KS16-biotin, KS15-biotin, and RS14-biotin (all at a final concentration of 10 μM). 30 μL of the supernatant was added to 10 μL of 4× loading buffer, boiled at 100°C for 5 minutes, and stored frozen at -20°C. 2 μL of antibody (Biotin, Vector, SP-3000) was added to the remaining protein lysate and mixed overnight at 4°C on a rotary mixer for approximately 16-18 hours. 30 μL of Protein G agarose beads (Roche, 11243233001) were placed in an EP tube and washed three times with Pierce RIPA lysis buffer to remove interference from the original stock solution. The protein incubated overnight with the antibody was then added to the agarose beads and incubated at 4°C for 2 hours to allow for full binding of the antibody to the protein. Centrifuge at 4000 rpm for 1 minute, aspirate the supernatant, add 600 μL of Pierce RIPA lysis buffer, gently invert, centrifuge, and remove the supernatant. Repeat this step three times to wash away nonspecifically bound proteins. Finally, add 30 μL of 1× loading buffer, mix thoroughly, and heat at 60°C for 20 minutes to denature the proteins. Store at -20°C. Proteins were analyzed by Western blotting (Myc-Tag (9B11) Mouse mAb, CST, 2276S; Anti-QD202, GL Biochem). The results are shown in Figure 1. The immunoprecipitation results show that ATP6V1B2 binders GS18, RS17, KS16, KS15, and RS14 (whose amino acid sequences are shown in SEQ ID NOs: 100-104, respectively) can all form immunoprecipitates with ATP6V1B2 protein. Example 2 Effects of ATP6V1B2 Binders on Synaptic Transmitter Transmission in Hippocampal Neurons This example demonstrates the therapeutic effects of ATP6V1B2 binders by examining changes in the frequency and amplitude of spontaneous excitatory postsynaptic currents in mouse hippocampal slices following treatment with ATP6V1B2 binders. Spontaneous excitatory postsynaptic currents are closely related to synaptic transmission, neuronal plasticity, and overall neural network activity. Effects on spontaneous excitatory postsynaptic currents suggest a therapeutic effect of ATP6V1B2 binders. Two- to three-month-old C57 mice were anesthetized with an intraperitoneal injection of 0.1-0.15 ml of 20% ulose. The brain tissue was then rapidly decapitated and placed in an ice-cold mixture of artificial cerebrospinal fluid (ACSF) pre-gassed with 95% O₂ and 5% CO₂ for 2 minutes. The ACSF composition was as follows: 11.7 mM NaCl, 0.36 mM KCl, 0.12 mM NaH₂PO₄, 0.25 mM CaCl₂, 0.12 mM MgCl₂, 25 mM NaHCO₃, and 11 mM glucose. 350 mm coronal hippocampal slices were cut using a vibratome. Hippocampal slices were placed in room temperature ACSF for at least 30 minutes to recover. The slices were then placed in a recording tank and continuously perfused with mixed ACSF at a rate of 2-2.5 ml / min. Under an Olympus BX51 upright microscope, hippocampal CA1 pyramidal neurons were blind-ligated and whole-cell patch clamp recordings were performed using an Axon 700B amplifier and a 1550B digital-to-analog converter. Spontaneous excitatory postsynaptic currents (sEPSCs) of pyramidal neurons were recorded with voltage clamp at a clamp voltage of -70 mV. After 5 minutes of sEPSC recording, the ATP6V1B2 binder described herein was administered for 5 minutes, followed by a 10-minute perfusion with ACSF. The recorded data were analyzed using Minianalysis software. The effects of the ATP6V1B2 binders described in this application on spontaneous excitatory post-synaptic currents (sEPSCs) were recorded in hippocampal slices. Figures 2 and 3 respectively show the effects of mutant 1 (whose amino acid sequence is shown in SEQ ID NO: 72) and GS18, RS17, KS16, KS15, and RS14 on sEPSCs. The results showed that the ATP6V1B2 binders described in this application significantly enhanced the frequency of sEPSCs, but had no significant effect on the amplitude of sEPSCs, and had similar effects to QD202. Example 3 Effect of ATP6V1B2 Binders on Lysosomal Acidity in HEK293 Cells The vesicular proton pump plays an important role in the acidification of lysosomes. As an important subunit structure of the vesicular proton pump, the ATP6V1B2 protein also plays an important role in the acidification of lysosomes in cells. Therefore, this example functionally verifies the binding and regulation between the ATP6V1B2 binder described in this application and the ATP6V1B2 protein by detecting the effect of QD202 on the acidity of lysosomes in HEK293 cells. The experimental materials and reagents used in this example are shown in the following table: LysoSensor TM The staining of Green DND-189 lysosomal green fluorescent probe is acidophilic and can accumulate in acidic organelles through protonation. Its fluorescence intensity is pH-dependent (acidophilic) as the degree of acidification of the organelles increases. The specific steps are as follows: HEK293 cells are seeded in 35mm glass-bottomed confocal culture dishes, cultured in DMEM high-glucose medium, and grown to a density of 70-80% at 37°C and 5% carbon dioxide content. A drug-containing cell culture medium with a final DMSO concentration of 0.1% is prepared, and the drug concentrations are 1nM V-ATPase inhibitor Bafilomycin A1, 5μM ATP6V1B2 binder described in this application, and 20μM ATP6V1B2 binder described in this application. The culture medium is discarded, and the drug-containing culture medium or blank control culture medium is added. The cells are incubated at 37°C and 5% carbon dioxide content for 3 hours. The culture medium is aspirated, washed once with PBS, and a probe-containing cell culture medium preheated at 37°C is added. The cells are incubated for 30 minutes in a growth state, and the staining solution is replaced with fresh culture medium and observed under a fluorescence microscope. 5-6 field-of-view images were collected for each dish of cells, and the average fluorescence intensity of the images was analyzed using ImageJ software. A total of 3 parallel experiments were performed. The experimental results are shown in Figure 3. The fluorescence intensity results show that the fluorescence intensity of the lysosomes in the group treated with the vesicular proton pump inhibitor Bafilomycin A1 was significantly weaker than that of the lysosomes in the untreated group. This suggests that inhibiting the vesicular proton pump can reduce lysosomal acidity. The fluorescence intensity of the lysosomes in the group treated with 20M QD202 was stronger than that of the lysosomes in the untreated group, indicating that lysosomal acidity was increased. Since the ATP6V1B2 binder described in this application has the same function as QD202, it suggests that the ATP6V1B2 binder described in this application may activate the function of the lysosomal vesicular proton pump by binding to the ATP6V1B2 protein, thereby increasing lysosomal acidity. Example 4: Effect of ATP6V1B2 Binding Agents on Improving Learning Ability In this example, an ATP6V1B2 binder was administered to mice, and their novel object recognition ability and water maze behavior were tested to evaluate the improvement effect of the ATP6V1B2 binder on learning ability. Novel object recognition test Novel object recognition was tested using an open field box (40 × 40 × 35 cm made of blue opaque plastic) with reference to the behavioral test protocol described in Leger, M., et al. Object recognition test in mice. Nat Protoc. 8, 2531-2537 (2013). On the first day, mice were placed in an open field box for 10 minutes of adaptation. On the second day, each mouse was gently placed in the center of the box, and two similar objects (No. 1 batteries) were placed in the central area. They were allowed to explore freely for 10 minutes, and then the mice were returned to their cages. After 3 hours, the mice were placed back in the box (one battery was replaced with a 10 cm high human-like toy) for 10 minutes for a memory retention test. The video was analyzed using Etho Vision XT 14 software to record the time the mice spent exploring the new / old objects. The discrimination index was calculated as (Tnovel-Tfamliar) / (Tnovel+Tfamiliar). Morris water maze test Morris water maze refers to the experimental scheme described by Qing-Feng Wu et al. in Fibroblast growth factor 13is a microtubule-stabilizing protein regulating neuronal polarization and migration.Cell.149,1549-1564 (2012). The test was carried out in a room with a fixed environment in a circular pool filled with water (120 cm in diameter, 30 cm in depth, made opaque by adding titanium dioxide, and maintained at 21±1°C). The experiment was divided into an adaptation period (1 day), a training period (5 days) and a testing period (1 day). Adaptation period: The platform was placed 0.5 cm above the water surface and the mice were guided to the platform. Training day: The platform was placed 0.5 cm underwater and the mice were trained to find the platform. When the mouse reached the platform, the timing was stopped. If the mouse did not reach the platform within 1 minute, it was guided to the platform and stayed on the platform for 30 seconds. Training sessions were conducted four times daily (8:00 AM - 4:00 PM). Mice were placed into the water from different entry points each time, with at least 30 minutes between each session. Training sessions were conducted for a total of five days, with the order of entry points varying from day to day. Experimental day: The experiment was conducted 24 hours after the end of the training day. The platform was removed, and the mouse was placed into the water from an untrained entry point. The video recording was performed for one minute. The video recordings were analyzed using Etho Vision XT 14 software, and parameters including escape latency to enter the target quadrant, number of platform crossings, and time spent in the target quadrant were recorded. 4.1 Oral administration of peptides Ten-month-old APP / PS1 transgenic mice (purchased from Shanghai Model Organisms) were selected and divided equally into three groups. These mice were gavage-administered with PBS buffer (Group 2), different ATP6V1B2 binders described herein (Group 3, administered at a dose of 5 mg / kg), and donepezil (Group 4, administered at a dose of 1 mg / kg). Ten-month-old C57 BL / 6 mice that did not receive any agent were served as controls (Group 1). These four groups of mice were subjected to the above-mentioned behavioral tests. The results showed that after continuous oral administration of ATP6V1B2 binder for one week, APP / PS1 transgenic AD mice showed significant improvement in learning and cognitive functions in novel object recognition and water maze behavior tests. 4.2 Intravenous Injection of Peptides Ten-month-old APP / PS1 transgenic mice (purchased from Shanghai Model Organisms) were selected and divided equally into two groups. These mice were intravenously injected with PBS buffer (Group 2) and different ATP6V1B2 binders described in this application (Group 3, administered at a dose of 1 mg / kg). Ten-month-old C57 BL / 6 mice that were not intravenously injected with any reagent served as controls (Group 1). These four groups of mice were subjected to the above-mentioned behavioral tests. The results showed that after continuous intravenous injection of ATP6V1B2 binder for one week, APP / PS1 transgenic AD mice showed significant improvement in learning and cognitive functions in novel object recognition and water maze behavior tests. It can be seen that the ATP6V1B2 binders described in the present application (e.g., mutant 1, GS18, RS17, KS16, KS15 and RS14) have a significant improvement effect on learning ability, especially memory ability and cognitive ability. Example 5 Effects of ATP6V1B2 binders on postoperative function and cerebral infarction size in rats after MCAO This example demonstrates that intravenous administration of the ATP6V1B2 binders described herein can improve neurological and behavioral outcomes in rats after MCAO surgery. For example, they can improve neurobehavioral scores and reduce the size of cerebral infarction in rats after MCAO surgery. Middle cerebral artery occlusion (MCAO) is a commonly used stroke model in mice and rats. Edaravone is a widely used drug for the treatment of acute ischemic stroke. Experimental protocol: SD rats (male, 260-280 g) were randomly divided into sham + QD202 placebo group (n = 6), Model + placebo group (n = 6), positive control group Edaravone-5 mpk (n = 6), different ATP6V1B2 binders described in this application -1 mpk group (n = 6), different ATP6V1B2 binders described in this application -3 mpk group (n = 6), different ATP6V1B2 binders described in this application -5 mpk group (n = 6), sham group was sham operation group, Model group rats underwent right middle cerebral artery embolization (Middle Cerebral Artery Methods The edaravone group was given the drug once a day starting 3 days before surgery. On the day of surgery, the drug was given 6 times, 30 minutes before surgery, 30 minutes after surgery, and 60 minutes after surgery. The ATP6V1B2 binder group was given the drug once 30 minutes after surgery. Neurological function was scored 24 hours after surgery, and whole brain tissue was obtained for TTC staining to assess the infarct size. The MCAO model making process is as follows: (1) The animal is anesthetized by breathing, the neck skin is prepared, and iodine is used for disinfection; (2) The animal is fixed in the supine position and the neck is exposed; (3) A midline incision is made in the neck with scissors, and blunt separation is performed to expose the right common carotid artery, internal carotid artery and external carotid artery. The common carotid artery is clamped with an artery clamp, and a 5-0 suture is tied at the side of the external carotid artery near the brain, and a slipknot is tied at the external carotid artery near the common carotid bifurcation; (4) The internal carotid artery is clamped with an artery clamp, and the external carotid artery is cut between the two knots with microscissors. The suture is inserted into the internal carotid artery from the cut, and the internal carotid artery clamp is loosened and inserted into the middle cerebral artery until the suture bends. The slipknot at the common carotid bifurcation is tightened, and the embolization time is 60 minutes; (5) After the embolization is completed, the slipknot is slightly loosened, and after the suture is pulled out, the external carotid artery is immediately tied with a slipknot, the common carotid artery clamp is loosened to suture the neck wound, and iodine is used for disinfection; (6) An appropriate amount of glucose solution is injected after the operation to ensure the basic survival status of the animal. Neurobehavioral score results: Compared with the Model + placebo group, the neurobehavioral score results of the Sham + placebo group were lower than those of the Model + placebo group, with a statistically significant difference (p < 0.001). Compared with the Model + placebo group, the neurobehavioral score results of the positive control group Edaravone-5mpk group were lower than those of the Model + placebo group, with a statistically significant difference (p < 0.01). The neurobehavioral score results of the ATP6V1B2 binder-1mpk group described in this application were lower than those of the Model + placebo group. The neurobehavioral score results of the ATP6V1B2 binder-3mpk group described in this application and the ATP6V1B2 binder-5mpk group described in this application were both lower than those of the Model + placebo group. This example illustrates that the ATP6V1B2 binders described herein (eg, mutant 1, GS18, RS17, KS16, KS15, and RS14) have therapeutic effects on stroke. Example 6 Effect of ATP6V1B2 binders on scavenging ROS in an in vitro glucose-oxygen deprivation cell model This example illustrates that the ATP6V1B2 binder described in the present application has free radical scavenging and antioxidant effects, thereby having neuroprotective effects and therapeutic effects on stroke, and the effect is better than that of edaravone. Currently, based on the pathogenesis and disease process of ischemic stroke, the most widely used in vitro model is the neuronal oxygen-glucose deprivation model (OGD), which mainly simulates the occurrence process of ischemic damage in vivo. By treating cells with sugar and oxygen, it simulates the apoptosis of brain tissue induced by insufficient energy supply due to cerebral infarction. Cell culture: Mouse hippocampal HT22 cells were cultured in DMEM and 10% serum in a 5% CO2 incubator at 37°C. Oxygen-Glucose Deprivation (OGD) cell model: HT22 cells were cultured at a rate of approximately 1×10 5 HT22 cells were seeded into 96-well plates at a density of 100 μg / mL and cultured in DMEM with 10% serum in a 37°C incubator with 5% CO2 / 95% air for 24 hours. HT22 cells were placed in a glucose-free medium and then transferred to a sealed container containing a 5% CO2 / 95% N2 mixture. The sealed container was then placed in a 37°C incubator for 16 hours. Subsequently, the glucose-free medium was replaced with normal medium containing glucose and cultured in a 37°C incubator with 5% CO2 / 95% air for 24 hours, followed by reoxygenation. Experimental groups: Normally cultured HT22 cells served as the control group. OGD-treated HT22 cells were reoxygenated in normal culture medium and given solvent, the ATP6V1B2 binder described in this application (0.1 μM, 1 μM, 5 μM), and the ROS scavenger edaravone (200 μM), respectively. After reoxygenation for 24 hours, ROS was quantitatively detected. Quantitative detection of ROS: Reactive oxygen species (ROS) were detected using the Biyuntian Reactive Oxygen Species Detection Kit and the fluorescent probe DCFH-DA. DCFH-DA was diluted 1:1000 in serum-free culture medium to a final concentration of 10 μM. The culture medium was removed and the diluted DCFH-DA was added. The cells were incubated in a 37°C cell culture incubator for 20 minutes. The cells were washed three times with serum-free cell culture medium to fully remove the DCFH-DA that had not entered the cells. Observation was performed using a fluorescence microscope, and the mean fluorescence intensity was calculated using Image J software. Data analysis: Three parallel experiments were performed. The mean fluorescence intensity of the OGD plus solvent group was set as 100%. The fluorescence intensity of each group of cells was standardized and the values were presented as mean ± standard deviation. One-way ANOVA was used to perform nonparametric tests on the values of each group. Results: Compared with normally cultured HT22 cells, the ROS content in the solvent-treated group was significantly increased after OGD treatment. The ATP6V1B2 binders described in this application (e.g., mutant 1, GS18, RS17, KS16, KS15, and RS14) and positive control drugs can significantly inhibit the increase in ROS caused by OGD. Example 7 ATP6V1B2 binders regulate the production of sleep-related substances in the body This example illustrates that the ATP6V1B2 binders described in the present application can regulate sleep-related substances in the body, thereby being used to prevent and / or treat sleep disorders. Materials and methods Experimental Animals: Nine SPF-grade male C57 mice, aged 3-4 months, were provided by Shanghai Jihui Laboratory Animal Husbandry Co., Ltd. They were acclimated for 14 days in a clean animal room at the Shanghai Advanced Research Institute, with bedding changed weekly. During the experiment, the room temperature was maintained at 20-23°C, the humidity at 40-70%, and the lighting was on for 12 hours daily (8:00 AM to 8:00 PM). C57 mice were randomly divided into a PBS group, a single-dose group, and a multiple-dose group (3 mice per group). The mice were administered orally by gavage around 10:00 AM daily at a dose of 5 mg / kg of the ATP6V1B2 binder. Samples were collected one hour after the single-dose group and one hour after the last oral administration in the multiple-dose group, once daily for three consecutive days. Samples were collected one hour after the last oral administration in the PBS group, after a single oral administration of the corresponding volume of PBS. Sample processing methods were described in the kit instructions. The specific methods are as follows: Plasma: Blood was collected from the heart of anesthetized mice, placed in EDTA anticoagulant tubes, stored on ice, and centrifuged at 4000 × g for 10 minutes at 4°C. The supernatant was collected for analysis. Tissue homogenate: The mouse brain was obtained, and the cortex, hippocampus, striatum, and hypothalamus were sampled on ice. The tissue was rinsed with pre-chilled PBS (0.01 M, pH = 7.4) to remove residual blood. After weighing, the tissue was added with the corresponding volume of PBS containing protease inhibitors (at a weight-to-volume ratio of 1:9). The tissue was thoroughly ground using a tissue grinder and centrifuged at 5000 × g for 5-10 minutes at 4°C. The supernatant was collected for analysis. All samples were diluted 5-fold using the sample diluent provided in the kit for analysis. ELISA Kit Principle: Enzyme-linked immunosorbent assay (ELISA) kits were provided by Wuhan Elabscience Biotechnology Co., Ltd. (Elabscience). Kit Names and Catalog Numbers: Serotonin / 5-hydroxytryptamine (5-HT) ELISA Kit (E-EL-0033c), Norepinephrine ELISA Kit (E-EL-0047c), Mouse Melatonin ELISA Kit (E-EL-M0788c). The kits utilize a competitive ELISA method. Antigen is coated onto an ELISA plate. During the assay, the antigen in the sample (or standard) competes with the coated antigen for binding sites on a biotin-labeled monoclonal antibody, and free components are washed away. Avidin labeled with horseradish peroxidase is added, and biotin specifically binds to the avidin to form an immune complex, and free components are washed away. A chromogenic substrate (TMB) is added, which develops a blue color under the catalysis of horseradish peroxidase and turns yellow upon addition of the stop solution. The OD value was measured at a wavelength of 450 nm using a microplate reader. The antigen concentration was inversely proportional to the OD 450 value. The concentration of the antigen in the sample was calculated by drawing a standard curve. ELISA kit operation steps: refer to the kit instructions, the specific method is as follows: 1. Set up standard wells, blank wells, and sample wells. Add 50 μL of serially diluted standard to the standard wells, 50 μL of standard and sample diluent to the blank wells, and 50 μL of the test sample to the remaining wells. Immediately add 50 μL of biotinylated antibody working solution to each well. Cover the plate with film and incubate at 37°C for 45 minutes. 2. Drain all liquid from the wells and pat dry on clean absorbent paper. Add 350 μL of wash buffer to each well and soak for 1 minute. Aspirate or discard the liquid from the plate and pat dry. Repeat the wash step three times. 3. Add 100 μL of HRP enzyme conjugate working solution to each well, cover the ELISA plate, and incubate at 37°C for 30 minutes. 4. Shake off all liquid in the wells and wash the plate 5 times using the same method as step 2. 5. Add 90 μL of substrate solution (TMB) to each well, cover the ELISA plate, and incubate at 37°C in the dark for 15 minutes. 6. Add 50 μL of stop solution to each well to terminate the reaction. 7. Immediately measure the optical density (OD value) of each well using a microplate reader at a wavelength of 450 nm. 8. Calculate the average OD value of the standard and sample replicates, fit the standard curve of the four-parameter logistic function, and calculate the concentration of the sample to be tested. The results show that the ATP6V1B2 binders described in the present application (e.g., mutant 1, GS18, RS17, KS16, KS15, and RS14) can regulate the secretion of sleep-related substances in the body, such as serotonin, norepinephrine, and melatonin.

Claims

1. A binding agent comprising a molecule capable of binding to ATP6V1B2 and / or a functionally active fragment thereof, wherein the molecule comprises the amino acid sequence shown in SEQ ID NO: 19 and / or a variant thereof, wherein X is any amino acid.

2. The binding agent according to claim 1, wherein the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 20-24 and / or variants thereof, wherein X is any amino acid.

3. The binding agent according to any one of claims 1-2, wherein the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 25-30 and / or variants thereof, wherein X is any amino acid.

4. The binding agent according to any one of claims 1 to 3, wherein the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 31 to 35 and / or variants thereof.

5. The binding agent according to any one of claims 1 to 4, wherein the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 36 to 41 and / or variants thereof.

6. The binding agent according to any one of claims 1 to 5, wherein the molecule comprises the amino acid sequence shown in any one of SEQ ID NOs: 42 to 48 and / or variants thereof.

7. The binding agent of any one of claims 1-6, wherein the molecule comprises a protein and / or a polypeptide.

8. The binding agent of any one of claims 1-7, wherein the molecule comprises a multimer.

9. The binding agent of claims 1-8, wherein the multimer comprises a homodimer.

10. The binding agent according to any one of claims 1 to 9, wherein the cysteine in the amino acid sequence of the molecule does not have a sulfhydryl blocking modification.

11. The binding agent according to any one of claims 1 to 10, wherein the serine in the amino acid sequence of the molecule does not have a phosphorylation modification.

12. The binding agent of any one of claims 1-11, wherein the molecule comprises a fusion protein and / or a fusion polypeptide.

13. The binding agent according to any one of claims 12, wherein the fusion protein and / or fusion polypeptide comprises a molecule capable of being transported across the blood-brain barrier to the brain and / or a molecule capable of crossing a cell membrane.

14. The binding agent according to claim 13, wherein the molecule capable of being transported across the blood-brain barrier to the brain and / or the molecule capable of crossing the cell membrane comprises a polypeptide.

15. The binding agent according to any one of claims 14, wherein the molecule capable of being transported to the brain across the blood-brain barrier and / or the molecule capable of crossing the cell membrane comprises a cell-penetrating peptide.

16. The binding agent according to claim 15, wherein the cell-penetrating peptide comprises an amino acid sequence as shown in any one of SEQ ID NOs: 79-84 and / or variants thereof.

17. The binding agent according to any one of claims 1 to 16, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 49 to 71 and / or a variant thereof, wherein X is any amino acid.

18. The binding agent according to any one of claims 1 to 17, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 72 to 78 and / or a variant thereof.

19. The binding agent according to any one of claims 1 to 18, wherein the ATP6V1B2 and / or functionally active fragments thereof are derived from mammals.

20. The binding agent according to any one of claims 1-19, wherein the ATP6V1B2 or a functionally active fragment thereof is derived from human or mouse.

21. The binding agent of any one of claims 1-20, wherein the ATP6V1B2 comprises the amino acid sequence shown in SEQ ID NO: 8 or 16.

22. The binding agent according to any one of claims 1 to 21, wherein the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:

5.

23. The binding agent according to any one of claims 1 to 22, wherein the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the human ATP6V1B2 protein.

24. The binding agent according to any one of claims 1 to 22, wherein the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the mouse ATP6V1B2 protein.

25. The binding agent of any one of claims 1-24, wherein the functionally active fragment of ATP6V1B2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 10-11.

26. The binding agent according to any one of claims 1-25, wherein the ATP6V1B2 comprises an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO. 9 or 17.

27. The binding agent according to any one of claims 1 to 26, which is capable of modulating proton pump activity and / or function.

28. The binding agent according to any one of claims 1 to 27, which is capable of increasing the expression level and / or activity of a proton pump-related protein in a subject.

29. The binding agent of claim 28, wherein the expression level of the proton pump-associated protein is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry.

30. The binding agent according to any one of claims 28-29, wherein the expression level of the proton pump-associated protein is measured by using a substance selected from the following group: a primer capable of specifically amplifying a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a proton pump-associated protein, a small molecule that specifically binds to a proton pump-associated protein, a probe that specifically binds to a proton pump-associated protein, and a polypeptide that specifically binds to a proton pump-associated protein.

31. The binding agent according to any one of claims 1-30, which is capable of modulating the expression level and / or activity of ATP6V1B2.

32. The binding agent of any one of claims 1-31, which is capable of increasing the expression level and / or activity of ATP6V1B2 in a subject.

33. The binding agent according to any one of claims 31-32, wherein the expression level of ATP6V1B2 comprises the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein.

34. The binding agent of any one of claims 32-33, wherein the increase comprises an increase in the expression level and / or activity of ATP6V1B2 by at least about 10% compared to the expression level and / or activity of native ATP6V1B2 in the subject.

35. The binding agent of any one of claims 31-34, wherein the expression level of ATP6V1B2 is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry.

36. The binding agent according to any one of claims 31 to 35, wherein the expression level of ATP6V1B2 is measured by using a substance selected from the group consisting of: a primer capable of specifically amplifying the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 protein, a small molecule that specifically binds to the ATP6V1B2 protein, a probe that specifically binds to the ATP6V1B2 protein, and a polypeptide that specifically binds to the ATP6V1B2 protein.

37. The binding agent of any one of claims 1-36, which is capable of increasing neuronal synaptic transmitter release.

38. The binding agent of claim 37, wherein the increase comprises an increase of at least about 10% compared to the level of native neuronal synaptic transmitter release in the subject.

39. The binding agent of any one of claims 1-38, which increases the firing frequency of excitatory postsynaptic currents.

40. The binding agent of claim 39, wherein the increase comprises an increase of at least about 10% compared to the level of native excitatory postsynaptic current firing frequency in the subject.

41. An isolated polypeptide comprising the amino acid sequence as shown in SEQ ID NO: 19 and / or a variant thereof, wherein X is any amino acid.

42. The polypeptide according to claim 41, comprising the amino acid sequence shown in any one of SEQ ID NOs: 20-24 and / or variants thereof, wherein X is any amino acid.

43. The polypeptide according to any one of claims 41-42, comprising the amino acid sequence shown in any one of SEQ ID NOs: 25-30 and / or variants thereof, wherein X is any amino acid.

44. The polypeptide according to any one of claims 41 to 43, comprising the amino acid sequence shown in any one of SEQ ID NOs: 31 to 35 and / or variants thereof.

45. The polypeptide according to any one of claims 41 to 44, comprising the amino acid sequence shown in any one of SEQ ID NOs: 36 to 41 and / or variants thereof.

46. The polypeptide according to any one of claims 41 to 45, comprising the amino acid sequence shown in any one of SEQ ID NOs: 42 to 48 and / or variants thereof.

47. A fusion polypeptide comprising the polypeptide of any one of claims 41-46.

48. The fusion polypeptide according to claim 47, further comprising a molecule capable of being transported across the blood-brain barrier to the brain and / or a molecule capable of crossing cell membranes.

49. The fusion polypeptide according to claim 48, wherein the molecule transported to the brain across the blood-brain barrier and / or the molecule capable of crossing the cell membrane comprises a polypeptide.

50. The fusion polypeptide according to any one of claims 47 to 49, wherein the molecule capable of being transported across the blood-brain barrier to the brain and / or the molecule capable of crossing the cell membrane comprises a cell-penetrating peptide.

51. The fusion polypeptide according to any one of claims 47 to 50, wherein the cell-penetrating peptide comprises an amino acid sequence as shown in any one of SEQ ID NOs: 79 to 84 or a variant thereof.

52. The fusion polypeptide according to any one of claims 47 to 51, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 49 to 71 and / or variants thereof, wherein X is any amino acid.

53. The fusion polypeptide according to any one of claims 47 to 52, comprising the amino acid sequence shown in any one of SEQ ID NOs: 72 to 78 and / or variants thereof.

54. An immunoconjugate comprising the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, and / or the fusion polypeptide of any one of claims 47-53.

55. A nucleic acid molecule encoding the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, and / or the fusion polypeptide of any one of claims 47-53.

56. A vector comprising the nucleic acid molecule of claim 55.

57. A cell comprising the binding agent of any one of claims 1-40, the polypeptide or variant thereof of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, and / or the vector of claim 56.

58. A pharmaceutical combination comprising the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56 and / or the cell of claim 57.

59. A pharmaceutical composition comprising the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56 and / or the cell of claim 57, and optionally a pharmaceutically acceptable carrier.

60. A kit comprising the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56, the cell of claim 57, the pharmaceutical combination of claim 58 and / or the pharmaceutical composition of claim 59.

61. Use of the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56, the cell of claim 57, the pharmaceutical combination of claim 58 and / or the pharmaceutical composition of claim 59 in the preparation of a kit.

62. Use of the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56, the cell of claim 57, the pharmaceutical combination of claim 58 and / or the pharmaceutical composition of claim 59 in detecting ATP6V1B2.

63. A method for detecting ATP6V1B2 in a sample, comprising administering the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56, the cell of claim 57, the pharmaceutical combination of claim 58, the pharmaceutical composition of claim 59, and / or the kit of claim 60.

64. Use of the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56, the cell of claim 57, the pharmaceutical combination of claim 58 and / or the pharmaceutical composition of claim 59 in the preparation of a reagent.

65. The use according to claim 64, wherein the agent is used to improve learning ability, treat cognitive disorders, prevent and / or treat neurodegenerative diseases, and / or prevent and / or treat stroke.

66. The use according to any one of claims 64-65, wherein the cognitive impairment comprises early cognitive impairment (MCI), moderate cognitive impairment and severe cognitive impairment.

67. The use according to any one of claims 64-66, wherein the cognitive impairment comprises cognitive impairment caused by normal aging, Lewis body dementia (LBD), frontotemporal dementia and / or vascular dementia.

68. The use according to any one of claims 64 to 67, wherein the disease inducing cognitive impairment comprises Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD).

69. The use according to any one of claims 64-68, wherein the neurodegenerative disease comprises an acute neurodegenerative disease and a chronic neurodegenerative disease.

70. The method of any one of claims 64-69, wherein the neurodegenerative disease comprises a neurodegenerative disease caused by neuronal death and glial cell homeostasis, a neurodegenerative disease caused by aging, a neurodegenerative disease caused by affected CNS cell function, a neurodegenerative disease caused by abnormal intercellular communication, and / or a neurodegenerative disease caused by impaired cell motility.

71. The use according to any one of claims 64-70, wherein the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

72. The method of any one of claims 64-71, wherein the stroke comprises ischemic stroke and / or hemorrhagic stroke.

73. The use according to claim 72, wherein the ischemic stroke comprises cerebral infarction.

74. The use according to claim 73, wherein the cerebral infarction comprises lacunar infarction, ischemic infarction and / or hemorrhagic infarction.

75. The use according to any one of claims 72-74, wherein the ischemic stroke is caused by factors including thrombosis, embolism and / or hypotension.

76. The use according to claim 75, wherein the thrombus is caused by factors including atherosclerosis, aneurysm, vascular malformation, arteritis and / or vasospasm.

77. The method of claim 72, wherein the hemorrhagic stroke comprises intraparenchymal hemorrhage, intraventricular hemorrhage and / or subarachnoid hemorrhage.

78. The use according to claim 72 or claim 77, wherein the hemorrhagic stroke comprises primary cerebral hemorrhage and / or secondary cerebral hemorrhage.

79. The use according to any one of claims 72 and claims 77-78, wherein the hemorrhagic stroke comprises an aneurysmal subarachnoid hemorrhage.

80. The method of any one of claims 72 and 77-79, wherein the hemorrhagic stroke is caused by factors including vascular malformation, aneurysm, blood disease, cerebral amyloid angiopathy, abnormal vascular network at the base of the brain, cerebral arteritis, anticoagulation or thrombolytic therapy, and / or tumor stroke.

81. The method of any one of claims 65-80, wherein the stroke comprises damage caused by a stroke.

82. The use of claim 81, wherein the lesion comprises a lesion observed radiographically.

83. The use according to claim 82, wherein the lesions observed by imaging include intracerebral hematoma, intraventricular hemorrhage and / or subarachnoid hemorrhage.

84. The method according to any one of claims 82-83, wherein the lesions observed by imaging include edema, hematoma and / or mass effect.

85. The method according to any one of claims 82 to 84, wherein the lesions observed by imaging include dense artery sign, island band sign, blurred outline or decreased density of the lenticular nucleus, occlusion of cerebral perforating arterioles, edema and / or mass.

86. The use of claim 81, wherein the impairment comprises an impairment of learning ability.

87. The use according to claim 86, wherein the learning ability comprises cognitive ability, motor ability, memory ability and / or spatial exploration ability.

88. The use according to any one of claims 86-87, wherein the improvement in learning ability comprises an improvement in the subject's learning ability assessment score by at least about 50% compared to the subject's original learning ability assessment score.

89. The use according to any one of claims 86 to 88, wherein the assessment score of learning ability is measured by performing a test selected from the group consisting of a novel object recognition test and a water maze test.

90. The use according to claim 89, wherein the novel object recognition test evaluates the cognitive ability, motor ability and / or spatial exploration ability.

91. The use according to claim 89, wherein the water maze test evaluates the memory ability, motor ability and / or spatial exploration ability.

92. The use of any one of claims 64-91, wherein the subject comprises a mammal.

93. The use of any one of claims 64-92, wherein the subject comprises a human.

94. The method of any one of claims 64-93, wherein the subject comprises a non-cognitive disorder patient, a non-neurodegenerative disease patient, and / or a non-stroke patient.

95. The method of any one of claims 64-93, wherein the subject comprises a patient with cognitive impairment, a patient with a neurodegenerative disease, and / or a patient with a stroke.

96. The method of claim 95, wherein the subject comprises an Alzheimer's disease patient.

97. The method of any one of claims 64-96, wherein the subject is elderly.

98. The use according to any one of claims 64-97, wherein the agent is formulated for oral administration and / or injection.

99. The use according to any one of claims 64-98, wherein the agent is formulated for intravenous injection.

100. Use of the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56, the cell of claim 57, the pharmaceutical combination of claim 58 and / or the pharmaceutical composition of claim 59 in improving learning ability, treating cognitive disorders, treating neurodegenerative diseases, and preventing and / or treating stroke.

101. A method for improving learning ability, treating cognitive impairment, treating neurodegenerative diseases, preventing and / or treating stroke, comprising administering to a subject in need thereof the binding agent of any one of claims 1-40, the polypeptide of any one of claims 41-46, the fusion polypeptide of any one of claims 47-53, the immunoconjugate of claim 54, the nucleic acid molecule of claim 55, the vector of claim 56, the cell of claim 57, the pharmaceutical combination of claim 58 and / or the pharmaceutical composition of claim 59.

102. A binding agent comprising two parts, wherein a first part comprises a molecule that binds ATP6V1B2 and / or a functionally active fragment thereof and a second part comprises a molecule that delivers the first part.

103. The binding agent of claim 102, wherein the second portion has the function of delivering the first portion into cells and / or causing it to be transported across the blood-brain barrier to the brain.

104. The binding agent of any one of claims 102-103, wherein the second moiety is capable of delivering the first moiety into a cell expressing ATP6V1B2.

105. The binding agent of any one of claims 102-104, wherein the second moiety comprises a modifying group, a small molecule, a nanoparticle, an exosome, a virus, a nucleic acid, a protein, and / or a polypeptide.

106. The binding agent of claim 105, wherein the second portion comprises a group for PEGylation, lipidation and / or glycosylation of the first portion.

107. The binding agent of claim 105, wherein the nanoparticles comprise liposomes.

108. The binding agent of claim 107, wherein the liposome comprises a modified liposome, wherein the modification comprises a polypeptide modification, an antibody modification, a glycosyl modification, a ligand modification, a nucleic acid aptamer and / or a multi-targeting modification.

109. The binding agent of any one of claims 102-108, wherein the second moiety comprises a molecule that interferes with the physiological barrier function of the blood-brain barrier and / or a binding agent for a transporter protein on the blood-brain barrier.

110. The binding agent of claim 109, wherein the molecule that interferes with the physiological barrier function of the blood-brain barrier comprises an efflux inhibitor.

111. The binding agent of claim 109, wherein the transport proteins on the blood-brain barrier include insulin receptor (IR), transferrin receptor (TfR), low density lipoprotein receptor (LDLR), low density lipoprotein receptor-related protein 1 (LRP1) and LRP2, and diphtheria toxin receptor (DTR).

112. The binding agent of any one of claims 102-111, wherein the second moiety comprises a blood-brain barrier transporter binding protein.

113. The binding agent of any one of claims 102-112, wherein the second moiety comprises an antibody and / or antigen-binding fragment thereof that targets a transporter protein on the blood-brain barrier.

114. The binding agent of any one of claims 102-113, wherein the second moiety comprises an antibody and / or antigen-binding fragment thereof that targets transferrin receptor.

115. The binding agent of any one of claims 102-114, wherein the second moiety comprises a binding agent for a protein that mediates endocytosis.

116. The binding agent of any one of claims 102-115, wherein the second portion comprises a membrane-penetrating peptide.

117. The binding agent of claim 116, wherein the membrane-penetrating peptide comprises a membrane-penetrating peptide that enters the cell via an endocytic pathway and / or a direct penetration pathway.

118. The binding agent of any one of claims 116-117, wherein the cell-penetrating peptide comprises: Cationic cell-penetrating peptides, amphiphilic cell-penetrating peptides and / or hydrophobic cell-penetrating peptides.

119. The binding agent of any one of claims 116-118, wherein the cell-penetrating peptide comprises a linear peptide and / or a cyclic peptide.

120. The binding agent of any one of claims 116-119, wherein the cell-penetrating peptide comprises a cell-penetrating peptide derived from a TAT protein.

121. The binding agent according to any one of claims 102 to 120, wherein the second portion comprises the amino acid sequence shown in SEQ ID NO: 79 and / or a variant thereof.

122. The binding agent according to any one of claims 102-121, wherein the second portion comprises the amino acid sequence shown in any one of SEQ ID NOs: 80-84 and / or variants thereof.

123. The binding agent of any one of claims 102-122, wherein the first portion is attached to the second portion.

124. The binding agent of any one of claims 102-123, wherein the first portion is directly or indirectly attached to the second portion.

125. The binding agent according to any one of claims 102-124, wherein the first portion comprises an amino acid sequence as shown in any one of SEQ ID NOs: 19-30, 93-99, and / or variants thereof, wherein X is any amino acid.

126. The binding agent according to any one of claims 102-125, wherein the first portion comprises the amino acid sequence shown in any one of SEQ ID NOs: 31-48, SEQ ID NOs: 86-92 and / or variants thereof.

127. The binding agent according to any one of claims 102 to 126, wherein the first portion comprises the amino acid sequence shown in SEQ ID NO: 85 and / or a variant thereof.

128. The binding agent of any one of claims 102-127, wherein the first portion comprises a protein and / or a polypeptide.

129. The binding agent of any one of claims 102-128, wherein the first portion comprises a polymer.

130. The binding agent of claim 129, wherein the multimer comprises a homodimer.

131. The binding agent of any one of claims 102-130, wherein the cysteine in the first portion of the amino acid sequence does not have a sulfhydryl blocking modification.

132. The binding agent of any one of claims 102-131, wherein the serine in the first portion of the amino acid sequence does not have a phosphorylation modification.

133. The binding agent of any one of claims 102-132, wherein the first portion and the second portion form a fusion polypeptide.

134. The binding agent of any one of claims 102-133, wherein the binding agent comprises the amino acid sequence shown in any one of SEQ ID NOs: 100-104 and / or variants thereof.

135. The binding agent of any one of claims 102-134, wherein the ATP6V1B2 and / or functionally active fragments thereof are of mammalian origin.

136. The binding agent of any one of claims 102-135, wherein the ATP6V1B2 or a functionally active fragment thereof is derived from human or mouse.

137. The binding agent of any one of claims 102-136, wherein the ATP6V1B2 comprises the amino acid sequence shown in SEQ ID NO: 8 or 16.

138. The binding agent according to any one of claims 102-137, wherein the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:

5.

139. The binding agent according to any one of claims 102-138, wherein the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the human ATP6V1B2 protein.

140. The binding agent of any one of claims 102-138, wherein the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the mouse ATP6V1B2 protein.

141. The binding agent of any one of claims 102-140, wherein the functionally active fragment of ATP6V1B2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 10-11.

142. The binding agent of any one of claims 102-141, wherein the ATP6V1B2 comprises an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO. 9 or 17.

143. The binding agent of any one of claims 102-142, which is capable of modulating proton pump activity and / or function.

144. The binding agent according to any one of claims 102-143, which is capable of increasing the expression level and / or activity of a proton pump-related protein in a subject.

145. The binding agent of claim 144, wherein the expression level of the proton pump associated protein is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry.

146. The binding agent according to any one of claims 144-145, wherein the expression level of the proton pump-associated protein is measured by utilizing a substance selected from the following group: a primer capable of specifically amplifying a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a proton pump-associated protein, a small molecule that specifically binds to a proton pump-associated protein, a probe that specifically binds to a proton pump-associated protein, and a polypeptide that specifically binds to a proton pump-associated protein.

147. The binding agent of any one of claims 102-146, which is capable of modulating the expression level and / or activity of ATP6V1B2.

148. The binding agent of any one of claims 102-147, which is capable of increasing the expression level and / or activity of ATP6V1B2 in a subject.

149. The binding agent of any one of claims 147-148, wherein the expression level of ATP6V1B2 comprises the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene, and / or the expression level of the ATP6V1B2 protein.

150. The binding agent of any one of claims 148-149, wherein the increase comprises an increase in the expression level and / or activity of ATP6V1B2 by at least about 10% compared to the expression level and / or activity of native ATP6V1B2 in the subject.

151. The binding agent of any one of claims 147-150, wherein the expression level of ATP6V1B2 is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry.

152. The binding agent according to any one of claims 147-151, wherein the expression level of ATP6V1B2 is measured by using a substance selected from the group consisting of: a primer capable of specifically amplifying the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 protein, a small molecule that specifically binds to the ATP6V1B2 protein, a probe that specifically binds to the ATP6V1B2 protein, and a polypeptide that specifically binds to the ATP6V1B2 protein.

153. The binding agent of any one of claims 102-152, which is capable of increasing neuronal synaptic transmitter release.

154. The binding agent of claim 153, wherein the increase comprises an increase of at least about 10% compared to the level of native neuronal synaptic transmitter release in the subject.

155. The binding agent of any one of claims 153-154, which increases the firing frequency of excitatory postsynaptic currents.

156. The binding agent of claim 155, wherein the increase comprises an increase of at least about 10% compared to the level of native excitatory postsynaptic current firing frequency in the subject.

157. A fusion polypeptide comprising the amino acid sequence shown in any one of SEQ ID NOs: 100-104, wherein X is any amino acid.

158. The fusion polypeptide of claim 157, wherein the fusion polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 100-104.

159. An immunoconjugate comprising the binding agent of any one of claims 102-156 and / or the fusion polypeptide of any one of claims 157-158.

160. A nucleic acid molecule encoding the binding agent of any one of claims 102-156 and / or the fusion polypeptide of any one of claims 157-158.

161. A vector comprising the nucleic acid molecule of claim 160.

162. A cell comprising the binding agent of any one of claims 102-156 or a variant thereof, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, and / or the vector of claim 161.

163. A pharmaceutical combination comprising the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161 and / or the cell of claim 162.

164. A pharmaceutical composition comprising the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161 and / or the cell of claim 162, and optionally a pharmaceutically acceptable carrier.

165. A kit comprising the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161, the cell of claim 162, the pharmaceutical combination of claim 163 and / or the pharmaceutical composition of claim 164.

166. Use of the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161, the cell of claim 162, the drug combination of claim 163 and / or the pharmaceutical composition of claim 164 in the preparation of a kit.

167. Use of the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161, the cell of claim 162, the pharmaceutical combination of claim 163, the pharmaceutical composition of claim 164 and / or the kit of claim 165 in detecting ATP6V1B2.

168. A method for detecting ATP6V1B2 in a sample, comprising administering the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161, the cell of claim 162, the pharmaceutical combination of claim 163, the pharmaceutical composition of claim 164, and / or the kit of claim 165.

169. Use of the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161, the cell of claim 162, the pharmaceutical combination of claim 163 and / or the pharmaceutical composition of claim 164 in the preparation of a reagent.

170. The use according to claim 169, wherein the agent is used to improve learning ability, treat cognitive disorders, prevent and / or treat neurodegenerative diseases, and / or prevent and / or treat stroke.

171. The use according to any one of claims 169-170, wherein the cognitive impairment comprises early cognitive impairment (MCI), moderate cognitive impairment and severe cognitive impairment.

172. The use according to any one of claims 169-171, wherein the cognitive impairment comprises cognitive impairment due to normal aging, Lewis body dementia (LBD), frontotemporal dementia and / or vascular dementia.

173. The use according to any one of claims 169-172, wherein the disease inducing cognitive impairment comprises Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD).

174. The use according to any one of claims 169-173, wherein the neurodegenerative disease comprises an acute neurodegenerative disease and a chronic neurodegenerative disease.

175. The use according to any one of claims 169-174, wherein the neurodegenerative disease comprises a neurodegenerative disease caused by neuronal death and glial cell homeostasis, a neurodegenerative disease caused by aging, a neurodegenerative disease caused by affected CNS cell function, a neurodegenerative disease caused by abnormal intercellular communication and / or a neurodegenerative disease caused by impaired cell motility.

176. The use according to any one of claims 169-175, wherein the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

177. The use according to any one of claims 169-176, wherein the stroke comprises ischemic stroke and / or hemorrhagic stroke.

178. The use according to claim 177, wherein the ischemic stroke comprises cerebral infarction.

179. The method of claim 178, wherein the cerebral infarction comprises lacunar infarction, ischemic infarction and / or hemorrhagic infarction.

180. The use according to any one of claims 177-179, wherein the ischemic stroke is caused by factors including thrombosis, embolism and / or hypotension.

181. The use according to claim 180, wherein the thrombus is caused by factors including: atherosclerosis, aneurysm, vascular malformation, arteritis and / or vasospasm.

182. The method of claim 177, wherein the hemorrhagic stroke comprises intraparenchymal hemorrhage, intraventricular hemorrhage and / or subarachnoid hemorrhage.

183. The use according to claim 177 or claim 182, wherein the hemorrhagic stroke comprises primary cerebral hemorrhage and / or secondary cerebral hemorrhage.

184. The use of any one of claims 177 and claims 182-183, wherein the hemorrhagic stroke comprises an aneurysmal subarachnoid hemorrhage.

185. The use according to any one of claims 177 and claims 182-184, wherein the hemorrhagic stroke is caused by factors including: vascular malformation, aneurysm, blood disease, cerebral amyloid angiopathy, abnormal vascular network at the base of the brain, cerebral arteritis, anticoagulation or thrombolytic therapy and / or tumor stroke.

186. The use of any one of claims 169-185, wherein the stroke comprises damage caused by a stroke.

187. The use of claim 186, wherein the lesion comprises a lesion observed radiographically.

188. The method of claim 187, wherein the lesions observed by imaging include intracerebral hematoma, intraventricular hemorrhage and / or subarachnoid hemorrhage.

189. The method of any one of claims 187-188, wherein the lesions observed by imaging include edema, hematoma and / or mass effect.

190. The method according to any one of claims 187 to 189, wherein the lesions observed by imaging include dense artery sign, island band sign, blurred outline or decreased density of the lenticular nucleus, occlusion of cerebral perforating arterioles, edema and / or mass.

191. The use of claim 186, wherein the impairment comprises an impairment of learning ability.

192. The use according to claim 191, wherein the learning ability comprises cognitive ability, motor ability, memory ability and / or spatial exploration ability.

193. The use according to any one of claims 191-192, wherein the improvement in learning ability comprises an improvement in the subject's learning ability assessment score by at least about 50% compared to the subject's original learning ability assessment score.

194. The use according to any one of claims 192-193, wherein the assessment score of learning ability is measured by performing a test selected from the group consisting of a novel object recognition test and a water maze test.

195. The use according to claim 194, wherein the novel object recognition test evaluates the cognitive ability, motor ability and / or spatial exploration ability.

196. The use according to claim 194, wherein the water maze test evaluates the memory ability, motor ability and / or spatial exploration ability.

197. The use of any one of claims 169-196, wherein the subject comprises a mammal.

198. The use of any one of claims 169-197, wherein the subject comprises a human.

199. The method of any one of claims 169-198, wherein the subject comprises a non-cognitive disorder patient, a non-neurodegenerative disease patient, and / or a non-stroke patient.

200. The method of any one of claims 169-198, wherein the subject comprises a patient with cognitive impairment, a patient with a neurodegenerative disease, and / or a patient with a stroke.

201. The use of claim 200, wherein the subject comprises an Alzheimer's disease patient.

202. The method of any one of claims 169-201, wherein the subject is elderly.

203. The use according to any one of claims 169-202, wherein the agent is formulated for oral administration and / or injection.

204. The use according to any one of claims 169-203, wherein the agent is formulated for intravenous injection.

205. Use of the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161, the cell of claim 162, the drug combination of claim 163 and / or the pharmaceutical composition of claim 164 in improving learning ability, treating cognitive disorders, treating neurodegenerative diseases, and preventing and / or treating stroke.

206. A method for improving learning ability, treating cognitive disorders, treating neurodegenerative diseases, preventing and / or treating stroke, comprising administering to a subject in need thereof the binding agent of any one of claims 102-156, the fusion polypeptide of any one of claims 157-158, the immunoconjugate of claim 159, the nucleic acid molecule of claim 160, the vector of claim 161, the cell of claim 162, the pharmaceutical combination of claim 163 and / or the pharmaceutical composition of claim 164.

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