Isoflavone compositions and methods for treating neurodegenerative disorders

Abstract

The present disclosure provides technologies for treating or preventing a neurodegenerative disease, disorder, or condition, comprising administered to a subject an isoflavone agent and at least one additional agent, wherein the at least one additional agent is increases microglial Aβ uptake and / or reduces pro-inflammatory cytokine production.

Description

ISOFLAVONE COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE DISORDERS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 679,825, filed on August 6, 2024, which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] Neurodegenerative diseases are those diseases, disorders, or conditions that damage or destroy parts of the nervous system over time. In particular, many neurodegenerative disorders impact the brain, and include such disorders as Alzheimer’s Disease. Alzheimer’s Disease affects over 6.5 million people in the United States alone. SUMMARY

[0003] The World Health Organization reports that neurological conditions are currently “the leading cause of ill health and disability worldwide” (www.who.int / news / item / 14-03- 2024-over-1-in-3-people-affected-by-neurological-conditions--the-leading-cause-of-illness- and-disability- worldwide#:~:text=A%20major%20new%20study%20released,Study%20(GBD)%202021% 20data.), with incidence increasing at an alarming rate. As this incidence increases, so do reports of agents said to be able to ameliorate or mitigate one or more features of neurodegeneration. The present disclosure provides certain insights regarding surprising usefulness of various combinations of agents in the context of (e.g., to treat) neurological conditions and / or causes thereof.

[0004] Among other things, the present disclosure provides an insight that simultaneously reducing one or more aspects of neuroinflammation while increasing clearance of neurological plaques or components thereof (e.g., Aβ) may provide particular and surprising benefits in the context of neurological activity and / or conditions. Without wishing to be bound by any particular theory, for example, it is proposed that such mechanistic duality may beneficially reduce the onset, development, and / or progression of neurological condition(s) and / or may provide a robustness of benefit with unique advantages (e.g., improved outcome(s) and / or delayed onset for subject(s) suffering from or susceptible to such condition(s) and / or other benefit(s) for those who may not be, or may not be known to be, suffering from or susceptible thereto).

[0005] There remains a need for therapies useful in treating neurodegenerative disorders, such as Alzheimer’s Disease. The present disclosure encompasses, among other things, the surprising insight that particular combinations of small molecule compounds (including, for example, certain natural products) are particularly useful, and in some instances, synergistic with one another, to modulate levels of particular proteins in a manner useful for treating neurodegenerative disorders. The present disclosure further identifies the source of a problem with previous therapies in that they only impact a single target, whereas the present disclosure provides methods for treating neurodegenerative disorders that impact multiple targets.

[0006] For example, the present disclosure encompasses, among other things, the insight that concomitant reduction of amyloid-β (Aβ) and pro-inflammatory cytokines can lead to the prevention of neurodegeneration and progression of Alzheimer’s Disease. In particular, without wishing to be bound by theory, it is understood that Aβ deposition induced and neurodegeneration-induced reactive microgliosis activates microglia in the brain that leads to microglial clustering around Aβ plaques in patients suffering from Alzheimer’s Disease, leading to the release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα). Release of pro-inflammatory cytokines induces astrogliosis and neuroinflammation, which ultimately leads to neuronal cell death.

[0007] The present disclosure encompasses the surprising insight that promotion of microglial Aβ uptake and clearance coupled with simultaneous reduction of microglial pro- inflammatory activation can be a particularly therapeutic modality for treating neurodegenerative diseases, disorders, and conditions. While therapies have been proposed that address each of Aβ reduction and inflammation reduction, no provided therapies to date have been able to simultaneously improve microglial Aβ uptake with reduction of microglial pro-inflammatory activation. The present disclosure provides that achieve both of these goals.

[0008] Moreover, the present disclosure encompasses the insight that particular combinations of agents act in synergy to promote one or both of improving microglial Aβ uptake and / or reducing microglial pro-inflammatory activation That is, the present disclosure encompasses the surprising insight that an agent’s ability to promote microglial Aβ uptake is increased when administered in combination with certain agents described herein, relative to administration of the agent alone; similarly, an agent’s ability to reduce pro-inflammatory cytokine production (measured as TNFα concentration) is improved when administered in combination with certain agents described herein, relative to administration of the agent alone. In some embodiments, provided agents may, individually both promote microglial Aβ uptakeand reduce TNFα concentration, and one or both features may be improved when said agent is administered in combination with another agent described herein.

[0009] The present disclosure further encompasses the insight that promotion of microglial Aβ uptake and clearance coupled with simultaneous reduction of microglial pro-inflammatory activation can be a particularly effective modality for treating neurodegenerative diseases, disorders, and conditions or otherwise providing neurological benefit. While therapies have been proposed that address each of Aβ reduction and inflammation reduction, no provided therapies to date have been able to simultaneously improve microglial Aβ uptake with reduction of microglial pro-inflammatory activation. The present disclosure provides combinations of therapies that act in synergy for achieving both of these goals. It is understood that synergies are not necessarily quantified in an assay, but can act in concert to improve overall benefit to a subject utilizing provided technologies.

[0010] In some embodiments, the present disclosure provides methods of treating, preventing, or decreasing neuroinflammation. In some embodiments, neuroinflammation can be caused by or associated with neurodegenerative disorders (e.g., those described herein), other diseases, disorders, and conditions, such as viral infection, autoimmune disorders, mental stress (e.g., stress caused from overworking, lack of sleep, and the like), metabolic disorders, and injury, or aging. In some embodiments, neuroinflammation is caused by or associated with a viral infection. In some embodiments, a viral infection is a SARS-CoV-2 infection. In some embodiments neuroinflammation is characterized by microglia activation in the subject.

[0011] In some embodiments, the present disclosure provides technologies useful for treating or preventing neurodegenerative disorders. In some embodiments, the present disclosure provides technologies that provide neurological benefit. Neurological benefit is determined relative to an otherwise healthy subject that is not using provided technologies. In some embodiments, the present disclosure provides a method of treating or preventing a neurodegenerative disorder in a subject comprising administering an isoflavone agent and at least one additional agent, wherein the at least one additional agent increases microglial Aβ uptake and / or reduces pro-inflammatory cytokine production. Moreover, the present disclosure encompasses the surprising discovery that particular agents, when administered in combination with an isoflavone (e.g., ipriflavone), the microglial Aβ uptake is increased relative to administration of the agent alone. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein.

[0012] In some embodiments, provided compositions are useful for improving cognitive health of a subject. In some embodiments, provided compositions are useful for improving cognitive health of a healthy subject. In some embodiments, provided compositions are useful for supporting memory and recall in a subject. In some embodiments, the present disclosure provides a composition that maintains cognitive function in a subject. In some embodiments, the present disclosure provides a composition that prevents cognitive decline in a subject. In some embodiments, a subject is a healthy subject. In some embodiments, cognitive decline is age-related.

[0013] In some embodiments, the present disclosure provides a method for improving cognitive health of a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Aβ uptake and / or reduce pro- inflammatory cytokine production. In some embodiments, the first agent is an isoflavone (e.g., ipriflavone). In some embodiments, the present disclosure provides a method for improving cognitive health of a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an Aβ uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0014] In some embodiments, the present disclosure provides a method for supporting memory and recall in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Aβ uptake and / or reduce pro-inflammatory cytokine production. In some embodiments, the first agent is an isoflavone (e.g., ipriflavone). In some embodiments, the present disclosure provides a method for supporting memory and recall in a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an Aβ uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0015] In some embodiments, the present disclosure provides a method for maintaining cognitive function in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Aβ uptake and / orreduce pro-inflammatory cytokine production. In some embodiments, the first agent is an isoflavone (e.g., ipriflavone). In some embodiments, the present disclosure provides a method for maintaining cognitive function in a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an Aβ uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0016] In some embodiments, the present disclosure provides a method for preventing cognitive decline in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Aβ uptake and / or reduce pro-inflammatory cytokine production. In some embodiments, the first agent is an isoflavone (e.g., ipriflavone). In some embodiments, the present disclosure provides a method for preventing cognitive decline in a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an Aβ uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject. In some embodiments, cognitive decline is age-related.

[0017] In some embodiments, the present disclosure provides compositions for use in provided methods.

[0018] In some embodiments, the present disclosure provides a kit comprising an isoflavone agent (e.g., ipriflavone) and at least one additional agent that increases microglial Aβ uptake and / or reduces pro-inflammatory cytokine production.

[0019] In some embodiments, the present disclosure provides a combination comprising an isoflavone agent and at least on additional agent that increases microglial Aβ uptake and / or reduces pro-inflammatory cytokine production. In some embodiments, a kit further comprises one or more additional agents as described herein. BRIEF DESCRIPTION OF THE DRAWING

[0020] FIG.1A is a graph showing Aβ uptake upon treatment with urolithin A (#144 or #144 A) at 40μM or ipriflavone (NP-182) at 20μM, alone or in combination. A greater numberof stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0021] FIG.1B is a graph showing Aβ uptake upon treatment with cat's claw (#134) at 30μg / mL, urolithin A (#144 or #144 A) at 40μM or ipriflavone (NP-182) at 20μM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0022] FIG.1C is a graph showing Aβ uptake upon treatment with cat's claw (#134) at 30μg / mL, urolithin A (#144 or #144 A) at 40μM or ipriflavone (NP-182) at 20μM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0023] FIG.2A is a graph showing TNFα concentration upon treatment with varying doses of ipriflavone (NP-182). A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0024] FIG.2B is a graph showing Aβ uptake upon treatment of BV2 cells with varying doses of ipriflavone (NP-182). A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0025] FIG.2C is a graph showing Aβ uptake upon treatment of BV2 cells with varying doses of ipriflavone (NP-182).

[0026] FIG.2D is a graph showing Aβ uptake upon treatment of P2D3 cells with varying doses of ipriflavone (NP-182). A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0027] FIG.2E is a graph showing Aβ uptake upon treatment of P2D3 cells with varying doses of ipriflavone (NP-182).

[0028] FIG.3A is a graph showing TNFα levels upon treatment with ziprasidone (PRW- 1188) at 15µM and ipriflavone (NP-182) at 20µM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0029] FIG. 3B is a graph showing TNFα levels upon treatment with nifedipine (#4) at 20µM and ipriflavone (NP-182) at 20µM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0030] FIG.3C is a graph showing Aβ uptake upon treatment with fluticasone propionate (#7) at 15µM and ipriflavone (NP-182) at 25µM, alone or in combination. A greater numberof stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0031] FIG.3D is a graph showing Aβ uptake upon treatment with doxycycline H2O (NP- 640) at 40µM and ipriflavone (NP-182) at 25µM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0032] FIG.3E is a graph showing Aβ uptake upon treatment with dolutegravir (PRW- 1841) at 40µM and ipriflavone (NP-182) at 25µM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0033] FIG. 3F is a graph showing Aβ uptake upon treatment with nifediprine (#4) at 20µM and ipriflavone (NP-182) at 25µM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0034] FIG. 3G is a graph showing Aβ uptake upon treatment with ziprasidone tartrate (PRW-1188) at 20µM and ipriflavone (NP-182) at 25µM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0035] FIG.3H is a graph showing Aβ uptake upon treatment with nilotinib (#153) at 1µM and ipriflavone (NP-182) at 25µM, alone or in combination. A greater number of stars indicates a greater statistical significance. "ns" indicates a difference that is not statistically significant.

[0036] FIG. 4A. is a graph summarizing observations of behavior (from left to right: hyperactivity, distance, rearings (size), rearings (number), and number of fecal boli) in Open Field testing of test animals, presented in order from left to right for each observation: wild type control group treated with vehicle (group A), a 5xFAD mutated group treated with vehicle (group B), and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I).

[0037] FIG. 4B. is a graph summarizing observations of behavior (activity, left, and thigmotaxis, right) in Open Field testing of test animals, presented in order from left to right for each observation: wild type control group treated with vehicle (group A), a 5xFAD mutated group treated with vehicle (group B), and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I).

[0038] FIG.5. is a graph summarizing observations of nest building behavior for animals of a wild type control group treated with vehicle (group A), a 5xFAD mutated group treated with vehicle (group B), and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I).

[0039] FIG.6. is a pair of graphs summarizing observations in Morris Water Maze testing of test animals, including number of target zone crossings during the probe trial (top) and abidance in target quadrant during the probe trial (bottom), and abidance in each quadrant (NE quadrant was target quadrant). In each panel, data is presented for each treatment group from left to right in the following order: wild type control group treated with vehicle (group A); a 5xFAD mutated group treated with vehicle (group B); and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I).

[0040] FIGs. 7A-7B are graphs providing measurements of TNF-α levels in cortex and hippocampus samples (results from cortex and hippocampus samples are paired with cortex on the left and hippocampus on the right) obtained from animals of wild type control group treated with vehicle (group A), a 5xFAD mutated group treated with vehicle (group B), and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I). *p<0.05 relative to group B, **p<0.01 relative to group B, ***p<0.001 relative to group B. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0041] The present disclosure provides methods of treating neurodegenerative disorders, and kits useful for treating neurodegenerative disorders. The provided methods encompass the insight that provided methods and kits useful for practicing providing methods, are particularly useful for treating neurodegenerative disorders in that they concomitantly improve microglial amyloid-β (Aβ) uptake while reducing pro-inflammatory cytokine concentrations (e.g., tumor necrosis-alpha (TNFα) or chemokine concentration).

[0042] In some embodiments, provided technologies comprise or use an agent that increases microglial Aβ uptake, wherein said agent is an isoflavone agent, such as ipriflavone, and one or more additional compounds that increase Aβ uptake and / or reduce pro- inflammatory cytokine production. Compounds and Definitions

[0043] Compounds of this disclosure include those described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, thefollowing definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0044] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, tables provided herein show one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0045] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0046] About or approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "approximately" or "about" may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0047] Administering: As used herein, the term "administering" or "administration" typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriatecircumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be oral. In some embodiments, oral dosing can be immediate release, delayed release, or otherwise released in particular gastrointestinal locations, such as the stomach or the intestine.

[0048] Agent: As used herein, the term “agent”, may refer to a compound, molecule, or entity of any chemical class including, for example, a small molecule, polypeptide, nucleic acid, saccharide, lipid, metal, or a combination or complex thereof. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that comprises a polymer. In some embodiments, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that is substantially free of a particular polymer or polymeric moiety. In some embodiments, the term may refer to a compound, molecule, or entity that lacks or is substantially free of any polymer or polymeric moiety.

[0049] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0050] Analog: As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete way(s). In some embodiments, an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.

[0051] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-C14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include ,, a

[0052] Biological sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell- containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0053] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0054] Combination therapy: As used herein, the term “combination therapy” (or “combination treatment” or “combination” in reference to a pharmaceutical composition) refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality(ies)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity). In some embodiments, a combination is a single pharmaceutical composition comprising two or more agents. In some embodiments, a combination is two or more pharmaceutical compositions each comprising one or more agents.

[0055] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations arecomparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0056] Cycloaliphatic: As used herein, the term “cycloaliphatic” refers to a monocyclic C3-8hydrocarbon or a bicyclic C6-12hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.

[0057] Cycloalkyl: As used herein, the term “cycloalkyl” refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0058] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).

[0059] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional dosesin a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0060] Effective Amount: The term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.

[0061] Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0062] Halogen: The term “halogen” or “halo” means F, Cl, Br, or I.

[0063] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6, 10, or 14 π-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2- a]pyrimidinyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0064] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0065] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 6- to 10-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.

[0066] Modulator: The term “modulator,” as used herein, refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can cause an increase or decrease in the magnitude of acertain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator. For example, a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist.

[0067] Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

[0068] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0069] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0070] Pharmaceutical Composition or Composition: As used herein, the term “composition” refers to an agent or a combination of agents, formulated together with one or more acceptable carriers, including “pharmaceutically acceptable carriers.” In some embodiments, an active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, compositions or pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterilesolution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0071] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Those skilled in the art, reading the present disclosure, will appreciate that the term “pharmaceutical” (and its cognates such as “pharmaceutically”, etc.) does not require or imply review of or approval by any governmental agency charged with granting marketing approval for active agents and / or products with therapeutic or biologic activity. Rather, the term references a degree of such therapeutic or biologic activity, absent significant or otherwise problematic (e.g., in the context of a risk / benefit analysis as is understood in the art) toxicity when administered to a relevant population (e.g., a population in need of or that would otherwise benefit from such therapeutic or biologic activity). Specifically, those skilled in the art will appreciate that the term, as used herein, may refer, in some embodiments, to approved pharmaceutical agents. Alternatively or additionally, in some embodiments, the term may refer to what are sometimes referred to as nutraceutical agents or other “over-the counter” products. If the recipient (or recipient population) is other than human, the term may refer to veterinary agents.

[0072] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3– phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0073] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977, 66(1), 1-19; P. Gould, International J. of Pharmaceutics 1986, 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

[0074] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0075] Prevent or prevention: As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0076] Substituted or optionally substituted: As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or morehydrogens that are either explicit or implicit from the structure (e.g., refers to at least. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in some embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0077] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; – CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0– 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2;-P(O)2R°; -P(0)RO2; -0P(0)RO2; -OP(O)(ORO)2; SiR°3; -(Ci-4straight or branched alkylene)O-N(R°)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, - O(CH2)0-iPh, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0078] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)0 2R-, -(haloR*), -(CH2)0 2OH, -(CH2)0 2OR*, -(CH2)0-2CH(OR’)2, -O(haloR’), -CN, -N3, -(CH2)0 2C(O)R●, -(CH2)0 2C(O)OH, -(CH2)02C(O)OR*, -(CH2)0 2SR*, -(CH2)0 2SH, -(CH2)0 2NH2, -(CH2)0 2NHR*, -(CH2)02NR●2, - NO2, -SiR●3, OSiR●3, -C(O)SR●-(C1-4 straight or branched alkylene)C(O)OR●, or SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH2Ph, -0(CH2)0iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0079] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR+2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2 3O-, or -S(C(R●2))2 3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0080] Suitable substituents on the aliphatic group of R* include halogen, - R*, -(haloR*), -OH, -OR’, -O(haloR*), -CN. -C(O)OH, -C(O)OR’, -NH2, -NHR*, -NR’2,or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)01Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0081] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R*, -NR*2, -C(O)R*, -C(O)OR*, -C(O)C(O)R*, C(O)CH2C(O)R*, -S(O)2R*, -S(O)2NR*2, -C(S)NR*2, -C(NH)NR*2, or -N(R*)S(O)2R*; wherein each R1' is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R7. taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0082] Suitable substituents on the aliphatic group of R:are independently halogen, - R*. -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH. -C(O)OR*, -NH2, -NHR’, -NR*2. or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -0(CH2)0-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0083] Suffering from. An individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with and / or displays one or more symptoms of a disease, disorder, and / or condition.

[0084] Small molecule: As used herein, the term “small molecule” means a low molecularweight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0085] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide(e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and / or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.

[0086] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.

[0087] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0088] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.

[0089] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.

[0090] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;11C,13C or14C for12C;13N or15N for14N;17O or18O for16O;36Cl for35Cl or37Cl;18F for19F;131I for127I; etc.). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0091] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0092] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and / or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0093] Those skilled in the art will further appreciate that, in small molecule structures, the symbol , as used herein, refers to a point of attachment between two atoms. Additionally or alternatively, the symbol refers to a point of attachment ring in a spirocyclic manner.

[0094] Synergy: As used herein, the terms “synergy” or “synergies” refers to the effect that two or more agents have that is more than simply additive. That is, the effect observed when two or more agents are used is, in some embodiments, greater than when the agents are used in isolation or in other combinations. In some embodiments, synergies are measured quantitatively, such as by an assay described herein. In some embodiments, synergies may not show a quantitative change, but an overall improvement in, for example, treatment or prevention of a particular disease, disorder, or condition, is improved, relative to administration of an agent alone.

[0095] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delayonset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. Provided Combinations

[0096] In some embodiments, the present disclosure provides a method of treating or preventing a neurodegenerative disease, disorder, or condition in a subject comprising administering to a subject an isoflavone agent and at least one additional agent that is useful for increasing microglial amyloid-β (Aβ) uptake in the subject and / or reducing pro- inflammatory cytokine production in the subject.

[0097] Among other things, the present disclosure encompasses the insight that certain isoflavone agents, e.g., ipriflavone are particularly useful for promoting microglial Aβ uptake, and therefore are particularly useful in the treatment of neurodegenerative disorders, as described herein. Additionally, the present disclosure encompasses the surprising discovery that particular agents, when administered in combination with an isoflavone (e.g., ipriflavone), the microglial Aβ uptake is increased relative to administration of the agent alone.

[0098] Moreover, the present disclosure encompasses the insight that promotion of microglial Aβ uptake and clearance coupled with simultaneous reduction of microglial pro- inflammatory activation can be a particularly effective modality for treating neurodegenerative diseases, disorders, and conditions or otherwise providing neurological benefit. While therapies have been proposed that address each of Aβ reduction and inflammation reduction, no provided therapies to date have been able to simultaneously improve microglial Aβ uptake with reduction of microglial pro-inflammatory activation. The present disclosure provides combinations of agents that act in synergy for achieving both of these goals. It is understood that synergies are not necessarily quantified in an assay, but can act in concert to improve overall benefit to a subject utilizing provided technologies.

[0099] In some embodiments, the present disclosure provides technologies useful for treating or preventing neurodegenerative disorders. In some embodiments, the present disclosure provides technologies that provide neurological benefit. Neurological benefit is determined relative to an otherwise healthy subject that is not using provided technologies. Insome embodiments, the present disclosure provides a method of treating or preventing a neurodegenerative disorder in a subject comprising administering an isoflavone agent and at least one additional agent, wherein the at least one additional agent that increases microglial Aβ uptake and / or reduces pro-inflammatory cytokine production. Moreover, the present disclosure encompasses the surprising discovery that particular agents, when administered in combination with an isoflavone (e.g., ipriflavone), the microglial Aβ uptake is increased relative to administration of the agent alone. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein.

[0100] In some embodiments, the present disclosure provides a method of treating or preventing a neurodegenerative disorder comprising administering an isoflavone agent and at least one additional agent that is useful for increasing microglial amyloid-β (Aβ) uptake in the subject and / or for reducing pro-inflammatory cytokine production in the subject. In some embodiments, at least one additional agent are useful for increasing microglial amyloid-β (Aβ) uptake in the subject. In some embodiments, at least one additional agent are useful for reducing pro-inflammatory cytokine production in the subject. In some embodiments, one or more additional compounds are administered to the subject. In some embodiments, two, three, four, or five total compounds are administered to the subject, wherein each compound promotes microglial amyloid-β (Aβ) uptake in the subject and / or reduces pro-inflammatory cytokine production in the subject.

[0101] In some embodiments, provided methods comprise administering to a subject an isoflavone agent, and at least one additional agent that promotes microglial Aβ uptake, and one or more additional compounds reduce pro-inflammatory cytokine production. In some embodiments, provided methods comprise administering an isoflavone, and at least one additional agent that promotes microglial Aβ uptake, and one or more additional compounds reduce pro-inflammatory cytokine production.

[0102] As described herein, provided combinations further encompass a synergy when administering two or more compounds for improving microglial Aβ uptake, or reducing pro- inflammatory cytokine production relative to when a provided compound is administered alone. For example, administration of ipriflavone provides a first level of microglial Aβ uptake, but when ipriflavone is administered with another agent (e.g., urolithin A), the combination provides a second level of microglial Aβ uptake, wherein the second level is improved relative to (e.g., greater than) the first level.

[0103] As described herein, provided methods comprise administering to a subject for the treatment or preventing of a neurodegenerative disorder, an isoflavone agent. In some embodiments, an isoflavone agent is represented by formula I: R1aor a pharmaceutically acceptable salt thereof, wherein: R1ais H, OH, CF3, C1 to C6 alkoxy, C3 to C6 cycloalkyl, or C1 to C6 alkyl. In some embodiments, an isoflavone of Formula I is represented by Formula I-A: R1aI-A or a pharmaceutically acceptable salt thereof, wherein R1ais H, OH, CF3, C1to C6alkoxy, C3to C6 cycloalkyl, or C1 to C6 alkyl.

[0104] In some embodiments, R1ais H, OH, or C1to C6alkoxy. In some embodiments, R1ais H. In some embodiments, R1ais OH. In some embodiments, R1ais C1 to C6 alkoxy. In some embodiments, R1ais -O-C(H)(CH3)2.

[0105] In some embodiments, an isoflavone is ipriflavone:or a pharmaceutically acceptable salt thereof. Ipriflavone is a synthetic isoflavone that is also sold under the brand name Yambolap.

[0106] In some embodiments, an additional agent described herein is a urolithin. In some embodiments, a urolithin is represented by formula II:Formula II or a pharmaceutically acceptable salt thereof, wherein R1is -H, -OH, or -OR4; R2is -H, -OH, -OR4, -NH2, -NHR4, -SH, -SR4, -F, -Cl, -Br, -CN, -OCN, -O(CH2)nNH2, - O(CH2)nCH3, -C1 to C10 alkyl, C3-C6 cycloalkyl, -C6 to C12 aryl, -SOCH3, -SO2, -ONO2, -NO2, and -N3; R3is -H, -OH, or -OR4; R4is a C1 to C10 alkyl; R5is -H or -OR4; and n is from 1 to 10, wherein each alkyl, cycloalkyl, and aryl of R2is optionally substituted with one or more substituents selected from halogen, C1 to C10 alkyl, C3 to C6 cycloalkyl, and C6 to C12 aryl.

[0107] In some embodiments, R1is -H, R2is -OH, R3is -OH, and R5is -H.

[0108] In some embodiments, a urolithin of Formula II is urolithin A:or a pharmaceutically acceptable salt thereof.

[0109] Urolithin A (3,8-dihydroxy-6H-benzo[b,d]pyran-6-one) is produced, e.g., as a metabolite resulting from the transformation of ellagitannins by the gut bacterial. Ellagitannins are hydrolyzed in the gut to release ellagic acid, which in turn, is further processed by the gut microflora into urolithins. Urolithin A is commercially available (see, e.g., Sigma-Aldrich, SML1791) and can also be obtained by methods known to the skilled artisan.

[0110] In some embodiments, R1is -H, R2is -OH, R3is -H, and R5is -H.

[0111] In some embodiments, R1is -H, R2is -OCH3, R3is -H, and R5is -H.

[0112] In some embodiments, R1is -OH, R2is -OH, R3is -H, and R5is -H.

[0113] In some embodiments, R1is -OCH3, R2is -OCH3, R3is -H, and R5is -H.

[0114] In some embodiments, R1is -H, R2is -OH, R3is -OH, and R5is -H.

[0115] In some embodiments, R1is -H, R2is -OCH3, R3is -OCH3, and R5is -H.

[0116] In some embodiments, R1is -OH, R2is -OH, R3is -OCH3, and R5is -OCH3.

[0117] In some embodiments, R1is -H, R2is -OH, R3is -OCH3, and R5is -H.

[0118] In some embodiments, R1is -OH, R2is -OH, R3is -OH, and R5is -H.

[0119] In some embodiments, R1is -OCH3, R2is -OCH3, R3is -OCH3, and R5is -H.

[0120] In some embodiments, R1is -H, R2is -OH, R3is -OCH3, and R5is -OCH3.

[0121] In some embodiments, R1is -OH, R2is -OH, R3is -OCH3, and R5is -H.

[0122] In some embodiments, an additional agent described herein is a steroid. In some embodiments, an additional agent is a corticosteroid. In some embodiments, a corticosteroid is one selected from: MoDe

[0123] In some embodiments, an additional agent described herein is doxycycline or a doxycycline analog, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound that is doxycycline or a doxycycline analog is selected from:D D

[0124] In some embodiments, an additional agent is a triazole antifungal compound. In some embodiments, a compound is a triazole antifungal compound selected from:

[0125] In some embodiments, an additional agent described herein is selected from: Ketanserin tartrate hydrate

[0126] In some embodiments, an additional agent is a flavonoid. In some embodiments, a flavonoid is represented by formula III:III or a pharmaceutically acceptable salt thereof, wherein R7is H, CF3, OCH3, Cl, Br; R8is H, CF3, OH, OCH3, F, Cl, Br, or t-Bu; R9is H, CF3, Cl, Br, OH, C1to C6alkoxy, C3to C6cycloalkyl, C1to C6alkyl, or SCF3; R10is H, OH, CF3, C1to C6alkoxy, C3to C6cycloalkyl, or C1to C6alkyl; R11is H or NO2; R12is H, CH3, OH, OCH3, Cl or Br; R13is H, CH3, F, Cl or Br; andR14is H or OH.

[0127] In some embodiments, an additional agent is a flavonoid. In some embodiments, a flavonoid is represented by formula III, wherein: R7is H, CF3, OCH3, Cl, Br; R8is H, CF3, OH, OCH3, F, Cl, Br, or t-Bu; R9is H, CF3, Cl, Br, OH, C1to C6alkoxy, C3to C6cycloalkyl, C1to C6alkyl, or SCF3; R10is H, CF3, C1to C6alkoxy, C3to C6cycloalkyl, or C1to C6alkyl; R11is H or NO2; R12is H, CH3, OH, OCH3, Cl or Br; R13is H, CH3, F, Cl or Br; and R14is H or OH.

[0128] In some embodiments, a flavonoid represented by formula III is fisetin:or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, a flavonoid represented by formula III is quercetin:or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, an additional agent is cat’s claw (which is intended to refer to one or more extracts from cat’s claw or components thereof). Cat’s claw (Uncaria tomentosa) is a woody vine that can be found in the Amazon rain forest. Cat’s claw extracts or components thereof can be utilized for the treating or preventing (e.g., treating) of neurodegenerative diseases as disclosed herein. Cat’s claw extracts can be prepared from cat’s claw bark using conventional extraction methods. For example, the extraction process can involve use of 70% ethanol / distilled water at a ratio of 5:1. Components from cat’s claw extracts can be isolated using conventional methods, including, e.g., affinity fractionation andhigh-pressure liquid chromatography (HPLC), aqueous extraction, organic solvent extraction, and the like. The methods can also include assessment of the purity of the individual components using HPLC, mass spectroscopy and / or nuclear magnetic resonance (NMR) spectroscopy. The identity of individual components can be assessed using HPLC, -ve ion electrospray mass spectroscopy (relative intensity of the molecular ion given as a percentage), fourier transfer mass spectroscopy, ultraviolet spectroscopy,1H NMR,13C NMR, electrospray ionization time-of-flight mass spectroscopy (ESI-TOF), electron impact (EI) initiated mass spectroscopy, fast atom bombardment (FAB) mass spectroscopy, homonuclear correlation spectroscopy (COSY), constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation spectroscopy (CIGAR) and / or heteronuclear correlation spectroscopy (HETCOR).

[0131] In some embodiments, the cat’s claw component is a polyphenol. In some embodiments, the cat’s claw component is epicatechin dimers and variants thereof (known as proanthocyanidins). For example, the cat’s claw component can be proanthocyanidin B2 (epicatechin-4ß-8-epicatechin), proanthocyanidin B4 (i.e. catechin-4α → 8-epicatechin), proanthocyanidin C1 (i.e. epicatechin-4β→ 8-epicatechin-4β → 8-epicatechin). In some embodiments, the cat’s claw component is an epicatechin trimer (i.e. epicatechin-4β → 8- epicatechin-4β → 8-epicatechin), epiafzelechin-4β → 8-epicatechin, or an epicatechin tetramer (i.e. epicatechin-4β → 8-epicatechin-4β → 8-epicatechin-4β → 8-epicatechin). In some embodiments, the cat’s claw extract is PTI-00703 (Percepta).

[0132] In some embodiments, an additional agent is nicotinamide riboside or a pharmaceutically acceptable salt thereof. Nicotinamide riboside is a member of the Vitamin B3 family and has the following structure:

[0133] Nicotinamide riboside is an NAD+precursor, which is an essential coenzyme that plays important roles in various metabolic pathways. The importance of NAD+is reflected through the activity of NAD+-depleting enzymes, the mediators of aging, which are mostly induced by stress factors, such as DNA damage, oxidative stress, and inflammation. Pharmaceutically acceptable salts of nicotinamide riboside include, e.g.,nicotinamide-β-d-riboside chloride, nicotinamide-β-d-riboside bromide, thionicotinamide-β-d- riboside bromide, nicotinamide-β-d-riboside triacetate bromide, and thionicotinamide-β-d- riboside triacetate bromide. Nicotinamide riboside or pharmaceutically acceptable salts thereof are commercially available (e.g., Tru Niagen®) and can be obtained by methods known to the skilled artisan.

[0134] In some embodiments, an additional agent is a benzimidazole. In some embodiments, a benzimidazole is a compound represented by formula IV:or a pharmaceutically acceptable salt thereof, wherein R2ais phenyl or C1-C6alkyl, and X1is a bond, O, or S, and wherein the phenyl or alkyl are optionally substituted with halogen.

[0135] In some embodiments, a benzimidazole is selected from:

[0136] In some embodiments, an additional agent is selected from a urolithin, a flavonoid, a steroid, a dihydropyridine, doxycycline, a doxycycline analog, a triazole antifungal compound, cat’s claw, nicotinamide riboside, ziprasidone, ketanserin, dolutegravir, broxyquinoline, danthron, liothyronine, probucol, pergolide, clofazimine, enocitabine, and ufenamate, or pharmaceutically acceptable salts, solvates, and / or hydrates thereof.

[0137] In some embodiments, an additional agent described herein is selected from: urolithin A, fisetin, quercetin, cat’s claw, nicotinamide riboside, fluticasone propionate, doxycycline, albendazole, nifedipine, budesonide, nilotinib, ziprasidone, dolutegravir, or pharmaceutically acceptable salts, solvates, or hydrates thereof.

[0138] In some embodiments, an additional agent described herein is selected from: urolithin A, fluticasone propionate, doxycycline, albendazole, nifedipine, budesonide, nilotinib, ziprasidone, dolutegravir, or pharmaceutically acceptable salts, solvates, or hydrates thereof.

[0139] In some embodiments, a method described herein comprises administering to a subject ipriflavone and at least one additional agent selected from fluticasone propionate, ziprasidone, doxycycline, nifedipine, nilotinib, and dolutegravir, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof. In some embodiments, a method described herein comprises administering to a subject ipriflavone and fluticasone propionate. In some embodiments, a method described herein comprises administering to a subject ipriflavone and ziprasidone HCl. In some embodiments, a method described herein comprises administering to a subject ipriflavone and ziprasidone tartrate. In some embodiments, a method described herein comprises administering to a subject ipriflavone and doxycycline. In some embodiments, a method described herein comprises administering to a subject ipriflavone and nifedipine. In some embodiments, a method described herein comprises administering to a subject ipriflavoneand nilotinib. In some embodiments, a method described herein comprises administering to a subject ipriflavone and dolutegravir.

[0140] In some embodiments, one, two, three, or four additional agents are administered to a subject, wherein each of the one, two, or three additional compounds are useful for increasing microglial amyloid-β (Aβ) uptake in the subject and / or reducing pro-inflammatory cytokine production in the subject. In some embodiments, an additional agent is urolithin A. In some embodiments, an additional agent is fisetin. In some embodiments, an additional agent is quercetin. In some embodiments, an additional agent is dolutegravir. In some embodiments, urolithin A, fisetin, and quercetin are administered as additional agents to the subject. In some embodiments, In some embodiments, urolithin A, fisetin, quercetin, and dolutegravir are administered as additional agents to the subject.

[0141] In some embodiments, compounds and agents described herein are administered as separate dosage forms. In some embodiments, compounds and agents described herein are administered in a single dosage form.

[0142] As described herein, ipriflavone can be administered once, twice, or three or more times per day. In some embodiments, ipriflavone is administered in an amount that is about 1 mg to about 1500 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 100 mg to about 1000 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 100 mg to about 500 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 300 mg to about 800 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 600 mg to about 800 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 100 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 150 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 200 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 250 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 300 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 350 mg per day. In some embodiments, ipriflavone is administered at a dose of about 100 mg twice per day. In someembodiments, ipriflavone is administered at a dose of about 125 mg twice per day. In some embodiments, ipriflavone is administered at a dose of about 150 mg twice per day. In some embodiments, ipriflavone is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) once a day. In some embodiments, ipriflavone is administered at a dose of about 100 mg once per day. In some embodiments, ipriflavone is administered at a dose of about 125 mg once per day. In some embodiments, ipriflavone is administered at a dose of about 150 mg once per day.

[0143] Ipriflavone can be administered at a dose of about 0.5 mg to about 2500 mg (e.g., about 0.5 mg to about 20 mg, about 1 mg to about 10 mg, about 2 mg to about 6 mg, about 25 mg to about 500 mg, about 50 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 1500 mg, about 300 mg to about 1200 mg, about 400 mg to about 750 mg, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). In some embodiments, ipriflavone is administered in an amount that is from about 1 mg to about 1000 mg. In some embodiments, ipriflavone is administered in an amount that is about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg. In some embodiments, ipriflavone is administered in an amount of about 100 mg. In some embodiments, ipriflavone is administered in an amount of about 125 mg. In some embodiments, ipriflavone is administered in an amount of about 150 mg. In some embodiments, ipriflavone is administered in an amount of about 175 mg. In some embodiments, ipriflavone is administered in an amount of about 200 mg. In some embodiments, the present disclosure provides a composition that comprises about 100 mg of ipriflavone. In some embodiments, the present disclosure provides a composition that comprises about 125 mg of ipriflavone. In some embodiments, the present disclosure provides a composition that comprises about 150 mg of ipriflavone. In some embodiments, the present disclosure provides a composition that comprises about 200 mg of ipriflavone.

[0144] In some embodiments, ipriflavone is administered in an amount that is about 1.0 to about 5.0 mg / kg of the subject’s body weight. In some embodiments, ipriflavone is administered in an amount that is about 1.0 mg / kg, about 1.5 mg.kg, about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, about 4.0 mg / kg, about 4.5 mg / kg, or about 5.0 mg / kg.

[0145] In some embodiments, a provided agent is urolithin A. In some embodiments, urolithin A is administered in an amount that is from about 1 mg to about 2500 mg (e.g., about 1 mg to about 1000 mg, about 50 mg to about 2500 mg, about 10 mg to about 2400 mg, about 100 mg to about 2300 mg, about 130 mg to about 2100 mg, about 160 mg to about 1900, about 190 mg to about 1700 mg, about 220 mg to about 1500 mg, about 240 mg to about 1300 mg, about 260 mg to about 1100 mg, about 280 mg to about 1000 mg, about 300 mg to about 900 mg, about 1 mg, about 10 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). In some embodiments, urolithin A is administered in an amount that is about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg per day. In some embodiments, urolithin A is administered in an amount that is about 900 mg to about 1500 mg per day. In some embodiments, urolithin A is administered in an amount that is about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, or about 1000 mg per day.

[0146] As described herein, urolithin A can be administered once a day, twice a day, or three or more times a day. In some embodiments, urolithin A is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) twice a day. In some embodiments, urolithin A is administered at a dose of about 100 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 125 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 150 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 175 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 200 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 225 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 250 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) once a day. In some embodiments, urolithin A is administered at a dose of about 100 mg once per day. In some embodiments, urolithin A is administered at a dose of about 125 mg once per day. In some embodiments, urolithin A is administered at a dose of about 150 mg once per day. In some embodiments, urolithin A is administered at a dose of about 175 mg once per day. In someembodiments, urolithin A is administered at a dose of about 200 mg once per day. In some embodiments, urolithin A is administered at a dose of about 225 mg once per day. In some embodiments, urolithin A is administered at a dose of about 250 mg once per day. In some embodiments, urolithin A is administered at an amount of about 100 mg to about 5000 mg daily (e.g., about 100 mg to about 250 mg, about 200 mg to about 4000 mg, about 300 mg to about 3000 mg, about 400 mg to about 2500 mg, about 500 mg to about 2000 mg, about 550 mg to about 1500 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 700 mg, about 725 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg daily). In some embodiments, urolithin A is administered at an amount that is about 1000 mg daily (e.g., about 500 mg twice a day). In some embodiments, urolithin A is administered in an amount that is from about 1 mg to about 1000 mg per day. In some embodiments, urolithin A is administered at an amount of about 100 mg to about 5000 mg daily (e.g., about 100 mg to about 250 mg, about 200 mg to about 4000 mg, about 300 mg to about 3000 mg, about 400 mg to about 2500 mg, about 500 mg to about 2000 mg, about 550 mg to about 1500 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 700 mg, about 725 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg daily). In some embodiments, urolithin A is administered at an amount that is about 1000 mg daily (e.g., about 500 mg twice a day). In some embodiments, urolithin A is administered in an amount that is from about 1 mg to about 1000 mg per day. In some embodiments, the present disclosure provides a composition that comprises about 100 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 125 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 150 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 175 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 200 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 225 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 250 mg of urolithin A.

[0147] In some embodiments, urolithin A is administered at a dose of about 0.5 to about 65 mg / kg of the subject’s body weight (e.g., about 1 to about 60, about 1.5 to about 55, about 2 to about 50, about 2.5 to about 45, about 3 to about 40, about 3.5 to about 35, about 4 to about 30, about 4.5 to about 25, about 5 to about 20, about 5.5 to about 15, about 6 to about 12, or about 6.5 to about 10 mg / kg of the subject’s body weight). In some embodiments, urolithin Ais administered at a dose that is about 1.5 mg / kg to about 2 mg / kg of the subject’s body weight. In some embodiments, urolithin A is administered at a dose that is about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, or about 2 mg / kg of the subject’s body weight.

[0148] In some embodiments, nicotinamide riboside is administered at a dose of about 1 mg to about 2500 mg (e.g., about 10 mg to about 1000 mg about 50 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 500 mg). In some embodiments, nicotinamide riboside is administered at a dose of about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg per day.

[0149] Dolutegravir can be administered at a dose of about 0.5 mg to about 2500 mg (e.g., about 0.5 mg to about 20 mg, about 1 mg to about 10 mg, about 2 mg to about 6 mg, about 25 mg to about 500 mg, about 50 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 1500 mg, about 300 mg to about 1200 mg, about 400 mg to about 750 mg, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). In some embodiments, dolutegravir is administered in an amount that is from about 1 mg to about 1000 mg. In some embodiments, dolutegravir is administered in an amount that is from about 25 mg to about 300 mg. In some embodiments, dolutegravir is administered in an amount that is from about 50 mg to about 250 mg. In some embodiments, dolutegravir is administered in an amount that is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg. In some embodiments, dolutegravir is administered in an amount of about 10 mg. In some embodiments, dolutegravir is administered in an amount of about 25 mg. In some embodiments, dolutegravir is administered in an amount of about 50 mg. In some embodiments, dolutegravir is administered in an amount of about 75 mg. In some embodiments, dolutegravir is administered in an amount of about 100 mg. In some embodiments, dolutegravir is administered in an amount of about 125 mg. In some embodiments, dolutegravir is administered in an amount of about 150 mg. In some embodiments, dolutegravir is administered in an amount of about 175 mg. In some embodiments, dolutegravir is administered in an amount of about 200 mg. In some embodiments, dolutegravir is administered in an amount of about 225 mg. In someembodiments, dolutegravir is administered in an amount of about 250 mg. In some embodiments, dolutegravir is administered in an amount of about 275 mg. In some embodiments, dolutegravir is administered in an amount of about 300 mg.

[0150] In some embodiments, dolutegravir is administered in an amount that is about 1 mg to about 1500 mg per day. In some embodiments, dolutegravir is administered in an amount that is about 100 mg to about 1000 mg per day. In some embodiments, dolutegravir is administered in an amount that is about 100 mg to about 500 mg per day. In some embodiments, dolutegravir is administered in an amount that is about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg per day. In some embodiments, dolutegravir is administered in an amount that is about 300 mg to about 800 mg per day. In some embodiments, dolutegravir is administered in an amount that is about 600 mg to about 800 mg per day. In some embodiments, dolutegravir is administered in an amount that is about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg per day. In some embodiments, dolutegravir is administered in an amount of about 100 mg per day. In some embodiments, dolutegravir is administered in an amount of about 150 mg per day. In some embodiments, dolutegravir is administered in an amount of about 200 mg per day. In some embodiments, dolutegravir is administered in an amount of about 250 mg per day. In some embodiments, dolutegravir is administered in an amount of about 300 mg per day. In some embodiments, the present disclosure provides a composition that comprises about 100 mg of dolutegravir. In some embodiments, the present disclosure provides a composition that comprises about 125 mg of dolutegravir. In some embodiments, the present disclosure provides a composition that comprises about 150 mg of dolutegravir. In some embodiments, the present disclosure provides a composition that comprises about 200 mg of dolutegravir.

[0151] As described herein, dolutegravir can be administered once, twice, or three or more times per day. For example, in some embodiments, dolutegravir is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) twice a day. In some embodiments, dolutegravir is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) once a day. In some embodiments, dolutegravir is administered at a dose of about 100 mg once per day. In some embodiments, dolutegravir is administered at a dose of about 125 mg once per day. In some embodiments, dolutegravir is administered at a dose of about 150 mg once per day. In some embodiments, dolutegravir is administered at an amount of about 100 mg toabout 5000 mg daily (e.g., about 100 mg to about 250 mg, about 200 mg to about 4000 mg, about 300 mg to about 3000 mg, about 400 mg to about 2500 mg, about 500 mg to about 2000 mg, about 550 mg to about 1500 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 700 mg, about 725 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg daily). In some embodiments, dolutegravir is administered at an amount that is about 1000 mg daily (e.g., about 500 mg twice a day). In some embodiments, dolutegravir is administered in an amount that is from about 25 mg to about 300 mg. In some embodiments, dolutegravir is administered in an amount that is from about 50 mg to about 250 mg. In some embodiments, dolutegravir is administered in an amount that is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

[0152] In some embodiments, dolutegravir is administered in an amount that is from about 1 mg / kg to about 100 mg / kg of the subject’s body weight. In some embodiments, dolutegravir is administered in an amount that is from about 0.1 mg / kg to about 10 mg / kg of the subject’s body weight. In some embodiments, dolutegravir is administered in an amount that is about 0.1 mg / kg to about 5 mg / kg of the subject’s body weight. In some embodiments, dolutegravir is administered in an amount that is about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.50 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, about 2.25 mg / kg about 2.5 mg / kg, about 2.75 mg / kg, about 3.0 mg / kg, about 3.25 mg / kg, about 3.5 mg / kg, about 3.75 mg / kg, about 4.0 mg / kg, about 4.25 mg / kg, about 4.5 mg / kg, about 4.75 mg / kg, or about 5.0 mg / kg of the subject’s body weight.

[0153] As described herein, doxycycline can be administered once, twice, or three or more times per day. In some embodiments, doxycycline is administered in an amount that is from about 100 mg to about 300 mg. In some embodiments, doxycycline is administered in an amount that is from about 50 mg to about 300 mg. In some embodiments, doxycycline is administered in an amount that is about 150 mg to about 250 mg. In some embodiments, doxycycline is administered in an amount that is about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg. In some embodiments, doxycycline is administered in an amount that is from about 50 mg to about 100 mg.

[0154] In some embodiments, doxycycline is administered in an amount that is from about 1 mg / kg to about 5 mg / kg of the subject’s body weight. In some embodiments, doxycycline is administered in an amount that is about 2 mg / kg to about 5 mg / kg of the subject’s body weight. In some embodiments, doxycycline is administered in an amount that is about 3.0 mg / kg, about3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg.kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, or about 4.0 mg / kg of the subject’s body weight.

[0155] As described herein, nifedipine can be administered once, twice, or three or more times per day. In some embodiments, nifedipine is administered in an amount that is from about 10 mg to about 200 mg. In some embodiments, nifedipine is administered in an amount that is from about 50 mg to about 200 mg. In some embodiments, nifedipine is administered in an amount that is from about 100 mg to about 150 mg. In some embodiments, nifedipine is administered in an amount that is about 100 mg, about 125 mg, or about 150 mg. In some embodiments, nifedipine is administered in an amount that is about 10 mg.

[0156] In some embodiments, nifedipine is administered in an amount that is from about 1 mg / kg to about 5 mg / kg of the subject’s body weight. In some embodiments, nifedipine is administered in an amount that is about 1 mg / kg to about 3 mg / kg of the subject’s body weight. In some embodiments, nifedipine is administered in an amount that is about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg about 1.8 mg / kg about 1.9 mg / kg about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, or about 3.0 mg / kg of the subject’s body weight.

[0157] As described herein, ziprasidone can be administered once, twice, or three or more times per day. In some embodiments, ziprasidone is administered in an amount that is from about 20 mg to about 1000 mg. In some embodiments, ziprasidone is administered in an amount that is from about 100 mg to about 1000 mg. In some embodiments, ziprasidone is administered in an amount that is from about 100 mg to about 500 mg. In some embodiments, ziprasidone is administered in an amount that is from about 200 mg to about 500 mg. In some embodiments, ziprasidone is administered in an amount that is about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments, ziprasidone is administered in an amount from about 20 mg to about 100 mg. In some embodiments, ziprasidone is administered in an amount from about 40 mg to about 200 mg.

[0158] In some embodiments, ziprasidone is administered in an amount that is from about 1 mg / kg to about 15 mg / kg of the subject’s body weight. In some embodiments, ziprasidone is administered in an amount that is from about 1 mg / kg to about 10 mg / kg of the subject’s body weight. In some embodiments, ziprasidone is administered in an amount that is about 1mg / kg, about 1.5 mg / kg, about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg about 4.0 mg / kg, about 4.5 mg / kg, about 5.0 mg / kg, about 5.5 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 8.5 mg / kg, about 9.0 mg / kg, about 9.5 mg / kg or about 10 mg / kg of the subject’s body weight.

[0159] In some embodiments, urolithin A is administered at an amount from about 1 mg to about 2500 mg per day, fisetin is administered at an amount from about 1 mg to about 2500 mg per day, quercetin is administered at an amount of about 1 mg to about 2500 mg per day, and ipriflavone is administered in an amount that is about 1 mg to about 1500 mg per day. In some embodiments, urolithin A is administered at an amount from about 1 mg to about 1000 mg per day, fisetin is administered at an amount from about 25 mg to about 500 mg per day, quercetin is administered at an amount from about 25 mg to about 500 mg per day, and ipriflavone is administered in an amount from about 100 mg to about 500 mg per day.

[0160] In some embodiments, urolithin A is administered at an amount from about 50 mg to about 200 mg per day, fisetin is administered at an amount from about 25 mg to about 250 mg per day, quercetin is administered at an amount from about 25 mg to about 250 mg per day, and ipriflavone is administered in an amount that is about 100 mg to about 300 mg per day. In some embodiments, urolithin A is administered at an amount of about 100 mg per day, fisetin is administered at an amount of about 50 mg per day, quercetin is administered at an amount of about 50 mg per day, and ipriflavone is administered in an amount of about 150 mg per day. In some embodiments, urolithin A is administered at an amount of about 200 mg per day, fisetin is administered at an amount of about 100 mg per day, quercetin is administered at an amount of about 100 mg per day, and ipriflavone is administered in an amount of about 300 mg per day.

[0161] In some embodiments, urolithin A is administered at an amount from about 1 mg to about 2500 mg per day, fisetin is administered at an amount from about 1 mg to about 2500 mg per day, quercetin is administered at an amount of about 1 mg to about 2500 mg per day, ipriflavone is administered in an amount that is about 1 mg to about 1500 mg per day, and dolutegravir is administered to the subject in an amount that is from about 1 mg to about 1500 mg per day. In some embodiments, urolithin A is administered at an amount from about 1 mg to about 1000 mg per day, fisetin is administered at an amount from about 25 mg to about 500 mg per day, quercetin is administered at an amount from about 25 mg to about 500 mg per day, ipriflavone is administered in an amount from about 100 mg to about 500 mg per day, anddolutegravir is administered to the subject in an amount that is from about 1 mg to about 1500 mg per day.

[0162] In some embodiments, urolithin A is administered at an amount from about 50 mg to about 200 mg per day, fisetin is administered at an amount from about 25 mg to about 250 mg per day, quercetin is administered at an amount from about 25 mg to about 250 mg per day, ipriflavone is administered in an amount that is about 100 mg to about 300 mg per day, and dolutegravir is administered to the subject in an amount that is from about 50 mg to about 300 mg per day. In some embodiments, urolithin A is administered at an amount of about 100 mg per day, fisetin is administered at an amount of about 50 mg per day, quercetin is administered at an amount of about 50 mg per day, ipriflavone is administered in an amount of about 150 mg per day, and dolutegravir is administered to the subject in an amount that is from about 50 mg to about 300 mg per day. In some embodiments, urolithin A is administered at an amount of about 200 mg per day, fisetin is administered at an amount of about 100 mg per day, quercetin is administered at an amount of about 100 mg per day, ipriflavone is administered in an amount of about 300 mg per day, and dolutegravir is administered to the subject in an amount that is from about 50 mg to about 300 mg per day.

[0163] In some embodiments, the present invention provides oral dosage forms such that the administration of a single oral dosage form constitutes administration of provided agents according to any of the above embodiments.

[0164] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form) and / or a hydrate form. Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Exemplary specific salt and hydrate forms intended to be contemplated within the scope of the present disclosure include, but are not limited to, ziprasidone hydrochloride, ziprasidone hydrochloride hydrate, ziprasidone tartrate, doxycycline hydrochloride, and doxycycline hydrate.

[0165] In some embodiments, provided compounds are administered in multiple oral dosage forms. For example, in some embodiments, an isoflavone agent (e.g., ipriflavone) and at least one additional agent are administered as separate dosage forms. In some embodiments, an isoflavone agent (e.g., ipriflavone) and at least one additional agent are administered as part of a single dosage form.

[0166] In some embodiments, a composition comprises an isoflavone agent (e.g., ipriflavone) and at least one additional agent, and optionally, one or more pharmaceutically acceptable carrier, adjuvant, or vehicle, as described further therein.

[0167] In some embodiments, the present disclosure provides a combination comprising: at least one oral dose of an isoflavone agent in an amount that is from about 1 mg to about 1500 mg; and at least one oral dose of an additional agent selected from: a urolithin, a flavonoid, a steroid, a dihydropyridine, doxycycline, a doxycycline analog, a triazole antifungal compound, cat’s claw, nicotinamide riboside, ziprasidone, ketanserin, dolutegravir, broxyquinoline, danthron, liothyronine, probucol, pergolide, clofazimine, enocitabine, and ufenamate, or pharmaceutically acceptable salts, solvates, and / or hydrates thereof. Uses, Formulation, and Administration Compositions

[0168] According to some embodiments, the present disclosure provides a composition comprising an isoflavone agent (e.g., ipriflavone) at least one additional agent described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.

[0169] In some embodiments, a composition comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, and ipriflavone, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, ipriflavone, or a pharmaceutically acceptable salt thereof, and quercetin, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises an amount of urolithin A that is from about 1 mg to about 2500 mg, an amount of fisetin that is from about 0.5 mg to about 2500 mg, an amount of ipriflavone that is from about 1 mg to about 1500 mg, and an amount of quercetin that is from about 1 mg to about 2500 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 1 mg to about 1000 mg, an amount of fisetin that is from about 25 mg to about 500 mg, an amount of ipriflavone that is from about 100 mg to about 500 mg, and an amount of quercetin that is from about 100 mg to about 500 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 2500 mg,an amount of fisetin that is from about 25 mg to about 500 mg, an amount of ipriflavone that is from about 100 mg to about 500 mg, and an amount of quercetin that is from about 100 mg to about 500 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 200 mg, an amount of fisetin that is from about 25 mg to about 250 mg, an amount of ipriflavone that is from about 100 mg to about 200 mg, and an amount of quercetin that is from about 25 mg to about 100 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 2500 mg, an amount of fisetin that is from about 25 mg to about 500 mg, an amount of ipriflavone that is from about 100 mg to about 500 mg, and an amount of quercetin that is from about 100 mg to about 500 mg. In some embodiments, the composition comprises an amount of urolithin A that is about 100 mg, an amount of fisetin that is about 50 mg, an amount of ipriflavone that is about 150 mg, and an amount of quercetin that is about 50 mg.

[0170] In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 2500 mg, an amount of fisetin that is from about 25 mg to about 500 mg, an amount of ipriflavone that is from about 100 mg to about 500 mg, an amount of quercetin that is from about 100 mg to about 500 mg, and an amount of dolutegravir that is from about 25 mg to about 1000 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 200 mg, an amount of fisetin that is from about 25 mg to about 250 mg, an amount of ipriflavone that is from about 100 mg to about 200 mg, an amount of quercetin that is from about 25 mg to about 100 mg, and an amount of dolutegravir that is from about 25 mg to about 1000 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 200 mg, an amount of fisetin that is from about 25 mg to about 250 mg, an amount of ipriflavone that is from about 100 mg to about 200 mg, an amount of quercetin that is from about 25 mg to about 100 mg, and an amount of dolutegravir that is from about 50 mg to about 300 mg.

[0171] Agents, compounds, and compositions, according to method of the present disclosure, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Agents and compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. An example carrier is FenuMATTM.

[0172] In some embodiments, provided compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, compositions described herein are administered without food. In other embodiments, compositions described herein are administered with food. Compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0173] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0174] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0175] The active agents can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0176] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active agents, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Kits

[0177] In some embodiments, the present disclosure provides a kit useful for the treatment of a neurodegenerative disorder. In some embodiments, a kit useful for the treatment of a neurodegenerative disorder comprises two or more compounds useful for increasing microglial amyloid-β (Aβ) uptake in the subject and / or reducing pro-inflammatory cytokine production.

[0178] In some embodiments, a kit comprises an isoflavone agent and at least one additional agent as described herein.

[0179] In some embodiments, a kit comprises an isoflavone agent and at least one additional agent that is selected from: urolithin A, fluticasone propionate, doxycycline, albendazole, nifedipine, budesonide, nilotinib, ziprasidone, dolutegravir, or pharmaceutically acceptable salts, solvates, or hydrates thereof.

[0180] In some embodiments, a kit comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, and ipriflavone, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, ipriflavone, or a pharmaceutically acceptable salt thereof, and quercetin, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, ipriflavone, or a pharmaceutically acceptable salt thereof, quercetin, or a pharmaceutically acceptable salt thereof, and dolutegravir, or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, a kit comprises oral dosage forms of the provided agents. In some embodiments, a kit further comprises instructions to consume one or two oral dosage forms daily. In some embodiments, a kit comprises instructions to consume one oral dosage form daily. In some embodiments, a kit comprises instructions to consume two oral dosage form daily. Neurodegenerative Disorders

[0182] Also provided herein are methods of treating or preventing (e.g., treating) neurodegenerative diseases in a subject in need thereof by administering or otherwise delivering to the subject two or more agents described herein.

[0183] Non-limiting examples of neurodegenerative diseases that can be treated or prevented using the methods disclosed herein include Alzheimer’s disease (AD), Parkinson's disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)), other trinucleotide repeat expansion disorders (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease,Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilder's disease, spinal cord injury, spinal muscular atrophy, SteeleRichardson-Olszewski disease, and Tabes dorsalis.

[0184] As is understood by those skilled in the art, effective prevention can involve delay of onset (e.g., of expected onset, as may be determined, for example, based on genetic, lifestyle, biomarker, or other factor(s)) of one or more features of a relevant disease, disorder or condition (e.g., of a neurodegenerative disease, as described herein); effective treatment can involve delay of onset (e.g., of expected onset) and / or reduction in frequency and / or severity of one or more such features.

[0185] Methods described in the present disclosure can include treatment of a disease or disorder per se, as well as treatment for one or more symptoms of the disease or disorder. “Treating” a disease does not require 100% abolition of the disease or disease symptoms in the subject. In some embodiments, treatment achieves relief or reduction in severity of one or more symptoms or features of the disease; typically, relevant relief or reduction is determined, for example, by a significant effect in an appropriate system (e.g., a model system) and / or an appropriate population (e.g., of human subjects or of animal models). In some embodiments, a composition described herein is shown to be effective in preventing or reducing cognitive decline as evidenced in a 5xFAD mouse model. For example, in some embodiments, a provided composition, when administered to a 5xFAD mouse, demonstrates substantially similar behavior as a wild-type mouse. A 5xFAD mouse model can also be used to assess cognitive health in a mouse as compared to a wild type mouse A 5xFAD mouse model can also be used to assess memory and recall in a mouse as compared to a wild type mouse A 5xFAD mouse model can also be used to assess cognitive function in a mouse as compared to a wild type mouse. In some embodiments, “treating” may be or comprise a delay in onset of symptoms or delay in progression of symptoms or the loss of function associated with the disease; alternatively or additionally, in some embodiments, “treating” may be or comprise a reduction in frequency and / or severity of one or more symptoms or features of the disease; alternatively or additionally, “treating” may be or comprise eliminating or reducing one or more side effects of a treatment or eliminating or reducing one or more direct or indirect effects of disease progression. In some embodiments, a subject who receives treatment in accordancewith the present disclosure may not exhibit signs of the disease but may be at risk for the disease.

[0186] In some embodiments, provided methods include selection of a subject, for example, by obtaining a sample from a candidate subject and testing the sample for an indication that the subject is suitable for selection. In some instances, the subject can be confirmed or identified, e.g. by a health care professional, as having a condition or disease or at risk for developing the condition or disease. In some instances multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some instances, subjects can be selected and / or referred by a medical practitioner (e.g., a general practitioner). Samples can include, for example, cells or populations of cells.

[0187] In some embodiments, following administration, the subject can be evaluated to detect, assess, or determine their level of disease. In some embodiments, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected. In some embodiments, treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and / or after treatment.

[0188] Upon improvement of a patient's condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary or desired. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0189] In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the loss of neurons and synapses in the cerebral cortex and atrophy in the temporal and parietal lobes. Histopathological findings of AD can include abnormal aggregates of amyloid plaques and neurofibrillary tangles.

[0190] Provided herein are methods of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a combination of an isoflavone agent and at least one additional agent as described herein. The methods can be used to treat at least one symptom of AD, reduce AD disease progression, reduce the deterioration of, maintain, or improve one or more bodily functions affected by AD, treat dementia or mild cognitive impairment (MCI) (e.g. dementia or MIC due to AD), or reduce the progressive decline of cognitive functions, including loss of declarative and procedural memory, decreased learningability, reduced attention span, severe impairment in thinking ability, judgment, and decision making. Also provided are methods of increasing the survival time of a subject having one or more symptoms of AD or reducing the levels of one or more biomarkers in a subject with AD (e.g., total tau or phospho-tau).

[0191] In some embodiments, the subject exhibits one or more symptoms associated with AD, have been diagnosed with AD, be suspected as having AD, or at risk for developing AD. The methods of treatment can further include determining or having determined that a subject has AD, has one or more symptoms associated with AD, or is at risk for developing AD.

[0192] Methods of diagnosing AD are known in the art. The subject can be diagnosed based on clinical history, family history, physical or neurological examinations. The subject can be confirmed or identified by a healthcare professional as having AD. Diagnosis of AD or determination of the risk of developing AD can be based upon neuroimaging, one or more cognitive tests (e.g., ADAS-Cog, MoCA, DSRS, MADCOMS, FAQ, or NPI-Q), or the presence of one or more biomarkers in the subject’s cerebrospinal fluid or blood samples. Exemplary biomarkers include amyloid-β 42 (Aβ42), total tau (T-tau), phosphorylated tau (P- tau), Aβ42 / 40 or amyloid precursor protein (APP) 669-711 / Aβ42 ratios, neurogranin, neurofilament light, and soluble insulin receptor. Diagnosis can also be based on detection of mutations in one or more genes associated with AD, for example, the presence of APOEε4 alleles or mutations in APP, Presenilin 1 (PSEN1), or Presenilin 2 (PSEN2). Inflammation within the brain, including increased reactivity of the resident microglia towards amyloid deposits, has been implicated in the pathogenesis and progression of AD. Therefore, diagnosis can also be based on the presence of markers of neuro-inflammation.

[0193] The treatment provided in the present disclosure can be initiated at any stage during disease progression. For example, treatment can be initiated prior to onset (e.g., for subjects at risk for developing AD), at symptom onset or immediately following detection of AD symptoms, or upon observation of any one or more symptoms that would lead a skilled practitioner to suspect that the subject may be developing AD (e.g., decline in cognitive functions, memory loss, reduced attention span). Treatment can also be initiated at later stages.

[0194] In some embodiments, a subject has not been diagnosed with any particular disease, disorder, or condition, e.g., a neurological disease, disorder, or condition. In some embodiments, a subject exhibits neurological benefit from provided regimens. For example, the present disclosure provides, in some embodiments, a method of improving neurological condition in a healthy subject, comprising administering to the subject an isoflavone agent andat least one additional agent that a promoter of Aβ uptake, or reduces pro-inflammatory cytokine production. In some embodiments, improvement of a neurological condition is determined relative to a subject who has not received an isoflavone agent and at least one additional agent that is a promoter of Aβ uptake or reduces pro-inflammatory cytokine production. In some embodiments, improvement of a neurological condition is determined in the subject relative to a baseline established prior to administration of an isoflavone agent and at least one additional agent that is a promoter of Aβ uptake or reduces pro-inflammatory cytokine production.

[0195] In some embodiments, provided compositions are useful for improving cognitive health of a subject. In some embodiments, provided compositions are useful for improving cognitive health of a healthy subject. In some embodiments, provided compositions are useful for supporting memory and recall in a subject. In some embodiments, the present disclosure provides a composition that maintains cognitive function in a subject. In some embodiments, the present disclosure provides a composition that prevents cognitive decline in a subject. In some embodiments, a subject is a healthy subject. In some embodiments, cognitive decline is age-related.

[0196] In some embodiments, the present disclosure provides a method for improving cognitive health of a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Aβ uptake and / or reduce pro- inflammatory cytokine production. In some embodiments, the first agent is an isoflavone (e.g., ipriflavone). In some embodiments, the present disclosure provides a method for improving cognitive health of a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an Aβ uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0197] In some embodiments, the present disclosure provides a method for supporting memory and recall in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Aβ uptake and / or reduce pro-inflammatory cytokine production. In some embodiments, the first agent is an isoflavone (e.g., ipriflavone). In some embodiments, the present disclosure provides a method for supporting memory and recall in a subject comprising administering a first agent and asecond agent, wherein one of the first agent or the second agent is an Aβ uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0198] In some embodiments, the present disclosure provides a method for maintaining cognitive function in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Aβ uptake and / or reduce pro-inflammatory cytokine production. In some embodiments, the first agent is an isoflavone (e.g., ipriflavone). In some embodiments, the present disclosure provides a method for maintaining cognitive function in a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an Aβ uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0199] In some embodiments, the present disclosure provides a method for preventing cognitive decline in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Aβ uptake and / or reduce pro-inflammatory cytokine production. In some embodiments, the first agent is an isoflavone (e.g., ipriflavone). In some embodiments, the present disclosure provides a method for preventing cognitive decline in a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an Aβ uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject. In some embodiments, cognitive decline is age-related.

[0200] In some embodiments, the present disclosure provides compositions for use in provided methods.

[0201] In some embodiments, a subject is healthy. In some embodiments, a subject is not at risk for developing a neurological disease, disorder, or condition. In some embodiments, a subject is determined not to be at risk of developing a neurological disease, disorder, or condition according to methods known to those of skill in the art. For example, in someembodiments, a subject is not at risk of developing a neurological disease, disorder, or condition if the subject has no familiar history of said neurological disease, disorder, or condition. In some embodiments, a subject is not at risk of developing a neurological disease, disorder, or condition if the subject exhibits particular biomarker (e.g., genetic biomarkers) associated with increased risk of developing a neurological disease, disorder, or condition. EXAMPLES

[0202] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Example 1: Effects of agents on release of pro-inflammatory cytokine release

[0203] The agents tested were Nifedipine (#4), a CDK inhibitor (#39), Urolithin A (#144), Ipriflavone (NP-182), Nilotinib (#153), and Ziprasidone tartrate (PRW-1188).

[0204] Effects of the agents, alone or in combination, on TNFα concentration were assessed (FIGs. 2A, 3A, 3B, 3H). After a 24 hour incubation, BV2 microglial cells were converted to a pro-inflammatory activation state by acute treatment with 1 μg / mL of Lipopolysaccharide (LPS) for 5 hours in the presence of a vehicle and one or more agents. A CDK inhibitor (#39) was tested as a positive control. Effects on inflammation were assessed by measuring levels of TNFα, via an ELISA assay on the conditioned cell media. Example 2: Effects of agents on release of microglial Aβ uptake

[0205] The agents tested were Nifedipine (#4), Fluticasone propionate (#7), Cat's Claw (#134), Urolithin A (#144), Nilotinib (#153), Ipriflavone (NP-182), Doxycycline H2O (NP- 640), Ziprasidone tartrate (PRW-1188), and Dolutegravir (PRW-1841).

[0206] The ability of the agents, alone or in combination, to increase microglial Aβ uptake was also assessed (FIGs 1A-1C, 2B-2E, 3C-3G). After a 24 hour incubation, BV2 microglial cells were treated with 300nM Aβ42 for 4 hours in the presence of a vehicle and one or more agents. Fluticasone propionate (#7) was tested as a positive control. Media was collected andthe cell lysate was collected with RIPA lysate buffer. Effects on Aβ42 uptake were assessed by measuring levels of Aβ42 via a Wako ELISA assay on the cell lysate. Example 3: In vivo assessment of provided combinations

[0207] 5xFAD mice bear five mutations, three in the amyloid precursor protein (APP695) gene [APP K670N / M671L (Swedish), I716V (Florida), V717I (London)] as well as two mutations in the presenilin 1 gene [PS1 M146L, L286V] (Oakley et al., 2006). The expression of the 5xFAD transgene is driven by the neuron specific Thy1 promoter. The five mutations cause an early onset of the cognitive decline and increasing Abeta 1-40 and 1-42 levels in the brain and cerebrospinal fluids, over age. Histological analysis revealed plaque load and beta sheet formation accompanied with neuroinflammation in 5xFAD mice.

[0208] Transgenic male and female (mixed sex) 5xFAD mice at an age of 5 months ±2 weeks, are randomly allocated to the study groups as shown in the table below:

[0209] All animals are treated per oral (p.o.) gavage for 18 weeks with either different combination treatments or vehicle (5% DMSO, 40% PEG300, 5% Tween-80, 50% Saline) on a daily basis for 18 weeks. Wild type animals from group A (n=10) and 5x FAD transgenic animals from group B (n=10) are treated p.o. with vehicle. Transgenic animals from group C- I (n=10 / group) receive a combination treatment of either 2 or 4 compounds via p.o. gavage on a daily basis for 18 weeks as following:

[0210] animals from group D are treated with Nifedipine and Ipriflavone (20 mg / kg and 150 mg / kg, respectively),

[0211] animals from group G are treated with Ipriflavone and Dolutegravir (150 mg / kg and 50 mg / kg, respectively),

[0212] and animals from group I are treated with Ipriflavone, Urolithin A, Fisetin, and Quercetin (150 mg / kg, 200 mg / kg, 100 mg / kg, and 100 mg / kg, respectively).

[0213] Concentrations of single doses of each T.I. are listed in the table below:

[0214] After 18 weeks of treatment, all animals are sacrificed ~3-4 hours (time-sensitive) after final dosing on last treatment day. CSF is collected from the cisterna magna and snap frozen on dry ice and stored at -80 °C for biochemical analysis. Terminal blood is collected by heart puncture in EDTA coated tubes. Blood plasma is collected by centrifugation (3000 x g for 10 minutes at room temperature) and plasma aliquots are transferred to 1.5 mL tubes, frozen on dry ice, and stored at -80 °C for biochemical analysis. Following transcardial perfusion with 0.9% saline, brains are removed and hemisected. The right hemibrains are post-fixed in 4 % paraformaldehyde in phosphate buffer (PFA / PB, pH 7.4) for two hours at room temperature, processed and embedded in cryomolds for histological evaluations. The left hemibrain of each animal is further dissected into cortex, hippocampus, and remaining brain, all parts are weighed, snap frozen on dry ice, and stored at -80°C for biochemical analysis.

[0215] For histological analysis, 8 brains per treatment group (from 72 animals in total) are then cryo-sectioned (12 levels with 5 sections each).5 sections per animal are then used for quantitative immunofluorescent labeling of amyloid plaques (6E10 or ThioS), microgliosis (Iba1), astrocytosis (GFAP), macrophages and monocytes (CD68) in cortex and subiculum. Additionally, 5 sections per animal are used for quantitative immunofluorescent labeling of synaptic health (synaptophysin, PSD95), and neuronal loss (NeuN) in cortex and subiculum.

[0216] For biochemical analyses, soluble and insoluble protein fractions are extracted from the left cortex and hippocampus of 8 brains per group (72 animals x 4 sample types, n=288 samples in total). Aβ 1-40 and Aβ 1-42 levels are analyzed separately in soluble and insolublecortical and hippocampal fractions using assays from Mesoscale Discovery (72 animals x 4 sample types = total of 288 samples per assay). In addition, a commercially available ELISA kit for Human β Amyloid (1-42, Wako) is used for analysis of Aβ 1-42 levels in soluble and insoluble cortical and hippocampal fractions (4 sample types x 72 samples = 288 samples in total). TNFα levels are measured in duplicates in soluble hippocampal and cortical samples using the V-PLEX Custom Mouse Cytokine assay by Mesoscale Discovery (2 x 72 samples = 144 samples in total as duplicates).

[0217] Measurement of Neurofilament light chain (NF-L) levels in terminal CSF samples are measured using the NF-L ELISA by Uman Diagnostics (total n= 72 samples as singlets). Example 4: In vivo assessment of provided combinations

[0218] Cohort I: A total of 40 transgenic male and female (mixed sex) 5xFAD mice at an age of 5 months ±2 weeks, as well as 10 wild type littermates of same sex and age were randomly allocated to the study groups as shown in the table below:

[0219] Cohorts II-V: In each cohort, a total of 40 transgenic male and female (mixed sex) 5xFAD mice at an age of 5 months ±2 weeks, as well as 10 wild type littermates of same sex and age were randomly allocated to the study groups as shown in the table below:

[0220] All animals were treated per oral (p.o.) gavage for 18 weeks with either different combination treatments or vehicle (5% DMSO, 40% PEG300, 5% Tween-80, 50% Saline) on a daily basis for 18 weeks. Wild type animals from group A (n=10) and 5x FAD transgenic animals from group B (n=10) were treated p.o. with vehicle. Transgenic animals from group I (n=10 / group) received a combination treatment of Ipriflavone, Urolithin A, Fisetin, and Quercetin (150 mg / kg, 200 mg / kg, 100 mg / kg, and 100 mg / kg, respectively) via p.o. gavage daily for 18 weeks.

[0221] At the end of the 18 weeks treatment period, all animals were subjected to a behavioral test battery. Exploratory behavior was assessed in the Open Field test, spatial learning and memory was tested in the Morris Water Maze, and general health and fine motor behavior was assayed in the Nest Building test.

[0222] After 18 weeks of treatment, all animals were sacrificed ~3-4 hours (time-sensitive) after final dosing on last treatment day. CSF was collected from the cisterna magna and snap frozen on dry ice and stored at -80 °C for biochemical analysis. Terminal blood was collected by heart puncture in EDTA coated tubes. Blood plasma was collected by centrifugation (3000 x g for 10 minutes at room temperature) and plasma aliquots were transferred to 1.5 mL tubes, frozen on dry ice, and stored at -80 °C for biochemical analysis. Following transcardial perfusion with 0.9% saline, brains were removed and hemisected. The right hemibrains were post-fixed in 4 % paraformaldehyde in phosphate buffer (PFA / PB, pH 7.4) for two hours at room temperature, processed and embedded in cryomolds for histological evaluations. The left hemibrain of each animal was further dissected into cortex, hippocampus, and remaining brain, all parts were weighed, snap frozen on dry ice, and stored at -80°C for biochemical analysis.

[0223] For histological analysis, 8 brains per treatment group (from 72 animals in total) were then cryo-sectioned (12 levels with 5 sections each).5 sections per animal were then used for quantitative immunofluorescent labeling of amyloid plaques (6E10 or ThioS), microgliosis (Iba1), astrocytosis (GFAP), macrophages and monocytes (CD68) in cortex and subiculum. Additionally, 5 sections per animal were used for quantitative immunofluorescent labeling of synaptic health (synaptophysin, PSD95), and neuronal loss (NeuN) in cortex and subiculum.

[0224] For biochemical analyses, soluble and insoluble protein fractions were extracted from the left cortex and hippocampus of 8 brains per group (72 animals x 4 sample types,n=288 samples in total). Abeta 1-40 and abeta 1-42 levels were analyzed separately in soluble and insoluble cortical and hippocampal fractions using assays from Mesoscale Discovery (72 animals x 4 sample types = total of 288 samples per assay). In addition, a commercially available ELISA kit for Human β Amyloid (1-42, Wako) was used for analysis of abeta 1-42 levels in soluble and insoluble cortical and hippocampal fractions (4 sample types x 72 samples = 288 samples in total). TNFα levels were measured in duplicates in hippocampus and cortex homogenates using the V-PLEX Custom Mouse Cytokine assay by Mesoscale Discovery (2 x 72 samples = 144 samples in total as duplicates).

[0225] Measurements of Neurofilament light chain (NF-L) levels in terminal CSF samples were performed using the NF-L ELISA by Uman Diagnostics (total n= 72 samples as singlets).

[0226] Bodyweight: Animals of all groups generally exhibited constant body weight throughout the in-life phase after some body weight fluctuations in the first two treatment weeks, indicating that treatment was tolerated well. Behavioral Test Battery

[0227] Open Field: The Open Field Test is a sensorimotor test that may be used to determine general activity levels, gross locomotor activity, and exploration habits in rodent models of central nervous system disorders indicating changes in anxiety, depression or motor performance. In this test, animals are exposed to a novel open space and the animal`s exploration activity is measured. For instance, differences in time spent in the center area (for rodents the most “threatening” part of the Open Field box) vs. the outside area may reflect strong differences in anxiety levels. Animals that spend a higher proportion of time in the outside area (higher thigmotaxis) may be considered more anxious. Changes in activity levels (e.g., distance traversed, activity and hyperactivity as well as duration and number of rearings) may also reflect emotional changes, as well as motor related changes. Reduced levels of these exploration parameters may be indicative of anxiety and depression.

[0228] An opaque Open Field Box (45 x 45 x 23.5 cm) in combination with a computerized video tracking system was used. Spontaneous activity and anxiety were assessed in the Open Field at the end of the 18 weeks treatment period by evaluating the following parameters for all animals: hyperactivity [s], activity [s], distance [m], rearings [s], rearings [n] and thigmotaxis [s], and number of fecal boli [n]. The open field test was performed prior to treatment on the testing day. The mice were brought to the room at least 45 minutes before the start of the testing. Each test session lasted for 5 minutes to check the mice's behavior in the new surroundings, as the first minutes of the Open Field test were the most suitable to displaythe exploratory behavior of the animals. After the testing session, the number of fecal boli was counted, as a measure of emotionality. The Open Field was cleaned with 70% Isopropanol after each mouse to get rid of odor traces. Testing was performed under standard room lighting conditions during the light phase of the circadian cycle.

[0229] 5xFAD mice of group B displayed significant age-dependent decreases in behavioral habituation to a novel environment. Animals of treatment group I displayed recovery of certain metrics of behavioral habituation to a novel environment relative to group B. Certain observations are summarized in the table below and in FIG.4A and FIG.4B.

[0230] Nest Building Behavior: Nesting behavior is an intrinsic behavior shown by rodents of both sexes that requires fine motor skills. The nest building test is a simple and versatile behavioral test performed in the home cage environment without the presence of the experimenter. In some cases, it is suitable for the evaluation of motor deficits, as well as changes in general health or welfare. It may be sensitive to environmental and physiological challenges, genetic mutations, and pharmacological interventions.

[0231] Mice were housed in cages containing wood chip bedding and a new 'nestlet', a 5 × 5 cm square of pressed cotton (treatment week 18). Mice were habituated to single-housing for at least one week prior to testing. No other nesting material (e.g. wood wool) was present. The nestlet was introduced on the day before testing, about 2 to 3 hours before the dark phase was initiated, and the nest building behavior was evaluated on the following day within 2 to 3 hours after the light phase started. The time span between introduction of the cotton square and evaluation of the nest status was the same for all examinations. The following morning thenests were assessed and rated by the experimenter according to a five-point scale (Deacon, NATURE PROTOCOLS, VOL.1, 2006, 1117): 1. Nestlet not noticeably touched (more than 90% intact). 2. Nestlet partially torn (50–90% remaining intact). 3. Nestlet mostly shredded but often no identifiable nest site: less than 50% of the Nestlet remains intact, but less than 90% is within a quarter of the cage floor area; i.e., the cotton is not gathered into a nest but is spread around the cage. 4. An identifiable but flat nest: more than 90% of the Nestlet is torn and the material is gathered into a nest, but the nest is flat, with walls higher than mouse body height (of a mouse curled up on its side) for less than 50% of its circumference. 5. A (near) perfect nest: more than 90% of the Nestlet is torn and the nest is a crater, with walls higher than mouse body height for more than 50% of its circumference. 5xFAD mice of group B displayed significant age-dependent degradation of nest building behavior. Vehicle treated transgenic animals (group B) exhibited lower mean nesting scores compared to vehicle treated wild type animals (group A). Animals treated with the combination treatments Nifedipine / Ipriflavone (group D); Ipriflavone / Urolithin A / Fisetin / Quercetin (group I) showed a trend towards improved nest building performance compared to vehicle treated transgenic animals. Certain observations are summarized in the table below and in FIG.5.

[0232] Morris Water Maze (MWM): The Morris water maze (MWM) is a widely used behavioral test to study spatial learning and memory in rodents. Typically, an animal learns to escape from the water by locating a hidden platform with help of visual cues. Lesions in distinct brain regions like hippocampus, striatum, basal forebrain, cerebellum and cerebral cortex have been shown to impair MWM accomplishment. As part of the test, escape latency, swim distance and thigmotaxis (indicative of strategy learning) were assessed during training days 1-4. Motor performance and emotional status (swim speed / velocity and floating, respectively) were assessed. Furthermore, target zone crossings and abidance in the target quadrant were quantified during the probe trial (day 5), and searching strategies during the acquisition training and probe trials were analyzed using the pathfinder software. One animal was excluded from analysis (an animal of Cohort III group C) due to a system error during recording. Analysis was performed for all animals (mixed-sex) and separated for sex. Based on low animal number of group C and F for male specific analysis, normality testing was omitted and Kruskal-Wallis followed by Dunn’s multiple comparison test was performed.

[0233] During treatment week 17, 4 MWM trials were performed on 4 consecutive days, plus 1 probe trial on day 5, using a computerized video tracking system. Escape latency, swim distance, and thigmotaxis (indicative of strategy learning), motor performance (swim speed / velocity) and emotional status (floating) were assessed. The MWM was performed prior to treatment on the respective testing days using the following pattern: four trials on each of four consecutive days were performed. In all trials, the platform was located in the northeast (NE) quadrant of the pool. Mice started from predefined positions (southeast (SE), southwest (SW), northwest (NW)). A single trial lasted for a maximum of 60 seconds. In case the mouse did not find the hidden, transparent platform within this time, the experimenter guided the mouse to the target. Mice were allowed to rest on the platform for 10-15 sec to orientate in the surrounding. Artificial landmarks were mounted above the walls of the pool to help the animals with their orientation. After the first 4 MWM trials (treated as training days), all mice were tested in a single probe trial on day 5, with the platform removed from the pool.

[0234] In some cases, mean performance of the animals during the first trial (trial 1) on each training day may be more reflective of long term memory capacity that is not masked by additional short term learning (during subsequent trials 2-4 on each training day). On the first trial day, wild type animals (group A) exhibited a slight trend towards improved learning behavior on all determined parameters compared to other treatment groups.

[0235] Target zone crossings and abidance in the target quadrant were quantified during the probe trial (day 5), and searching strategies during the acquisition training and probe trials were analyzed using the Pathfinder software. The number of crossings of the northeast (NE) target zone, the abidance in the NE target quadrant, as well as the abidance in all quadrants, were analyzed. Wild type animals of group A and transgenic animals of treatment group C, group H, and treatment group I exhibited increased target zone crossings and length of stay (abidance) in the target quadrant. When considering swim strategies based in their relevance to hippocampus-associated spatial learning using the Pathfinder tool, vehicle treated wild type animals (group A) exhibited highest cognitive scores per day during the training phase compared to all transgenic 5xFAD treatment groups, reaching statistical significance on training day 3 and 4 compared to vehicle treated transgenic animals (group B). The results are summarized in the table below and in FIG.6.

[0236] Vehicle-treated wild-type control animals (group A) exhibited significantly higher hippocampus-dependent search patterns on training days two, three, and four compared to vehicle-treated transgenic animals (group B). Comparison of transgenic animals of combination treatment groups and vehicle treated transgenic animals (group B) revealed a significantly increased use of hippocampus dependent search patterns: for Nifedipine / Ipriflavone (group D) and Ipriflavone / Dolutegravir (group G) treated animals on day 3. Ipriflavone / Urolithin A / Fisetin / Quercetin treatment (group I) exhibited increased use ofhippocampal search strategies on training day 4 compared to vehicle treated transgenic animals (group B). Certain observations of search strategies exhibited by animals of the various treatment group are provided in the table below.HHHHHHHHHHHippocampus dependent 0.00HHBiochemical and Histological Analysis

[0237] After 18 weeks of treatment, once all behavioral tests were completed, all animals were euthanized ~3-4 hours (time-sensitive) after a final dosing on the last treatment day by pentobarbital injection (600mg / kg). CSF, blood (plasma), and brain samples were collected as described below.

[0238] CSF Sampling: After confirmation of deep anesthesia, CSF was obtained by dissection of the muscles and exposure of the foramen magnum. Upon exposure, a Pasteur pipette was inserted in an approximate depth of 0.3 - 1 mm into the cisterna magna. CSF was collected by suction and capillary action until flow fully ceased in 0.2 ml polypropylene PCR tubes. The tubes were spun briefly and immediately frozen in an upright position on dry ice. The tubes were stored at -80 °C. CSF quality was documented as scores from 0 (no visible blood contamination) to 3 (severe blood contamination), and amount of CSF was estimated in µL.

[0239] Blood sampling: The thorax was opened and blood was collected by heart puncture with a 23-gauge needle. The needle was removed and the blood was transferred to the sample tube (MiniCollect® K2EDTA (potassium ethylenediaminetetraacetic acid). The tube was inverted thoroughly to facilitate homogeneous distribution of the EDTA and prevent clotting. The blood samples were centrifuged at 3,000 x g for 10 minutes at room temperature (22 °C). Plasma was transferred to pre-labeled 1.5 ml LoBind Eppendorf tubes (40 µl + 15 µl + rest aliquot), frozen on dry ice and stored at -80 °C.

[0240] Brain sampling: Animals were transcardially perfused with 0.9 % saline. To this end a 23-gauge needle connected to a bottle with 0.9% saline was inserted into the left ventricle. The thoracic aorta - between the lungs and the liver - was clamped with hemostatic forceps to block the blood flow from the heart to the abdomen but allowing the blood flow to the brain. The right atrium was opened with scissors. A constant pressure of 100 to 120 mm Hg was maintained on the perfusion solution by connecting the solution bottle to a manometer- controlled air compressor. Perfusion was continued until the skull surface had turned pale and only perfusion solution instead of blood was exiting of the right atrium. Following transcardial perfusion with 0.9% saline, brains were removed and hemisected. The left hemibrain of each animal was further dissected into cortex, hippocampus, and remaining brain. All parts were weighed, snap frozen on dry ice, and stored at -80°C for biochemical analysis. Soluble and insoluble protein fractions were extracted from the left cortex and hippocampus of 8 brains per group (72 animals x 4 sample types, n=288 samples in total). Aβ 1-40 and Aβ 1-42 levels were analyzed separately in soluble and insoluble cortical and hippocampal fractions using assays from Mesoscale Discovery (72 animals x 4 sample types = total of 288 samples per assay). In addition, a commercially available ELISA kit for Human β Amyloid (1-42, Wako) was used for analysis of Aβ 1-42 levels in soluble and insoluble cortical and hippocampal fractions (4 sample types x 72 samples = 288 samples in total). TNFα levels were measured in duplicatesin soluble hippocampal and cortical samples using the V-PLEX Custom Mouse Cytokine assay by Mesoscale Discovery (2 x 72 samples = 144 samples in total as duplicates).

[0241] Biochemical analysis: Frozen hippocampus and cortex samples were processed and homogenized by adding 19 volumes (hippocampus) or 9 volumes (cortex) of tissue homogenization buffer (THB; 250 mM Sucrose, 1 mM EDTA, 1 mM EGTA, 20 mM Tris pH 7.4) including 1x protease inhibitor (Calbiochem), to hippocampus / cortex samples. The tissue was homogenized with a beadmill (UPHO, Geneye) at 55Hz for 50sec. Three aliquots were stored at -80 °C until further use. For extraction of non-plaque associated proteins, 1 aliquot of THB homogenate was mixed with 1 part diethylamine (DEA) solution (0.4% DEA, 100mM NaCl). The mixture was centrifuged for 120 min at 20,000x g, 4 °C. The supernatant was neutralized with 1 / 10 of the volume 0.5 M Tris-HCl, pH 6.8 and vortexed briefly. Aliquots were stored at -80 °C as DEA fraction (soluble fraction). Total protein content was determined using Pierce™ BCA Protein Assay Kit (ThermoFisher). or extraction of deposited proteins, a second aliquot of THB homogenate was mixed with 2.2 parts cold formic acid (FA), sonicated for 30 sec on ice and centrifuged for 120 min at 20,000x g, 4 °C. The supernatant was mixed with 19 parts FA Neutralization Solution (1M Tris, 0.5 M Na2HPO4, 0.05% NaN3). Aliquots were stored at -80°C as FA fraction (insoluble fraction). For measurement of inflammation markers, the third aliquot of homogenate was substituted with Triton X-100 so that the final concentration was 1% in the homogenate. After vortexing and 10 min incubation on ice, the homogenates were cleared from cell debris by centrifugation at 20,800 x g at 4°C for 10 minutes in a tabletop centrifuge and the supernatants were collected for the measurement of cytokines and stored at -80°C until further use.

[0242] Human β Amyloid (1-42) levels were measured with ELISA Kit for Human β Amyloid 1-42 (Wako, 296-64401) in soluble and insoluble fractions of hippocampus and cortex. DEA samples were diluted 1:2500, FA samples 1:3000-1:10.000. Aβ levels in study samples were evaluated in comparison to calibration curves provided in the kit and are expressed as pg or ng per mg brain wet weight. Homogenates were analyzed for TNF-α in duplicates with a commercially available immunosorbent assay kit (K152QWD Mesoscale Discovery) according to the instructions of the manufacturer and evaluated in comparison to calibration curves provided in the kit and are expressed as pg / µg total protein or pg per mg brain wet weight.

[0243] TNFα levels were measured in duplicates in hippocampal and cortical protein fractions.

[0244] Transgenic animals of treatment group I exhibited a substantial effect on TNF-α production in the hippocampus extract in comparison to transgenic animals treated with vehicle (group B). This effect was especially significant when the level was normalized by total protein. Certain observations are summarized in FIGs.7A-7B.

[0245] The NF-light® (Neurofilament-light) ELISA 10-7001 CE from Uman Diagnostics was used for analysis of NF-L levels in CSF samples (n=72). CSF samples were diluted 1:30 in assay buffer and analyzed according to the manufacturers protocol in single replicates.

[0246] NF-L levels in CSF were significantly increased in vehicle treated transgenic animals (group B) compared to vehicle treated wild type animals (group A).

[0247] Histological Analysis: following fixation by immersion in freshly prepared 4% paraformaldehyde in phosphate buffer (PB; pH 7.4) for 2 hours at room temperature, right hemibrains of each animal (total n = 90 hemibrains) were transferred to 15 % sucrose / PBS and stored at 4 °C until sample was sunk to the bottom of the tube to ensure cryoprotection (usually overnight). Tissue blocks were then trimmed as needed, transferred to cryomolds, embedded in OCT medium, frozen in dry ice-cooled isopentane and stored in an ultra-deep freezer (set at -80 °C).

[0248] Frozen hemibrains from 8 animals per group (total n = 72 animals) were sectioned sagittally at 10 µm thickness on a Leica CM1950 or a Thermo Scientific NX70 cryotome, using following section scheme: five consecutive cryosections were collected and the next 25 sections per level were discarded. This collection scheme was repeated for 12 levels and was somewhat modified if required by unusual brain size. In total 12 x 5 = 60 sections were collected per hemibrain. Sectioning levels were chosen according to the brain atlas of Paxinos and Franklin (“The Mouse Brain in Stereotaxic Coordinates”, 2ndedition, 2001). Collection of sections started at a level ~0.2 mm lateral from midline and extend through the hemisphere, in order to ensure systematic random sampling through the target regions. Sections were stored at -20°C.

[0249] No significant differences between treatment groups were observed in the size of the different areas investigated, suggesting that section sampling was unbiased.

[0250] Immunofluorescence: For each incubation a uniform systematic random set of five sections per mouse was selected (one section each from levels 2, 4, 6, 8, 10). All sections were counterstained with the nuclear dye DAPI. Binding of primary antibodies was visualized using highly cross-absorbed secondary antibodies.

[0251] Protocol of Exp4711: CD68 + GFAP + Iba1 + ß-Amyloid + DAPI: All steps were executed in Dulbecco's phosphate buffered saline pH 7.5 (PBS) at room temperature unless noted otherwise. 1. cryo-sections were air-dried for 45 minutes and then washed in PBS for 10 minutes 2. reduction of autofluorescence by 4 minutes in cold 1 mg / ml sodium borohydride in PBS 3. sections were washed 3 x 5 minutes each in PBS 4. unspecific binding sites were blocked with M.O.M. blocking reagent (Vector Laboratories) 0.1% Tergitol in PBS for 60 minutes in a damp chamber 5. sections were washed 3 x 5 minutes each in PBS 6. sections were incubated with primary antibodies in M.O.M. diluent (Vector Laboratories) overnight at 4 °C in a damp chamber ° rat anti-CD68 monoclonal [FA-11] antibody (BioRad, MCA1957), 1:10000 ° goat anti-GFAP polyclonal (abcam, ab53554), 1:1000 ° guinea pig anti-Iba1 monoclonal [Gp311H9] antibody (Synaptic Systems, 234308), 1:3000 ° mouse anti-ßAmyloid monoclonal [6E10] antibody (BioLegend, B803001), 1:1000 7. sections were washed 3 x 5 minutes each in PBS 8. sections were incubated with secondary antibodies in M.O.M. diluent (Vector Laboratories) for 60 minutes in a damp chamber (light protected) ° donkey anti-rat IgG H+L DyLight 755-conjugated (Thermo Fisher, SA5- 10031), 1:500 ° donkey anti-goat IgG H+L Alexa Fluor 488-conjugated (abcam, ab150129), 1:500 ° donkey anti-guinea pig IgG H+L Cy3-conjugated, (Jackson Immunoresearch, 706-165-148), 1:500 ° donkey anti-mouse IgG H+L DyLight 650-conjugated (Thermo Scientific, SA5-10169), 1:500 9. sections were washed 3 x 5 minutes each in PBS (light protected) 10. sections were incubated with DAPI working solution for 15 minutes (light protected)11. sections were washed 2 x 5 minutes in PBS (light protected) 12. sections were washed for 5 minutes in ddH2O (light protected) 13. sections were automatically covered with Mowiol and coverslips (light protected) using a Leica CV5030 coverslipper.

[0252] Protocol of Exp4718: NeuN + PSD95 + Synaptophysin + DAPI: All steps were executed in Dulbecco's phosphate buffered saline pH 7.5 (PBS) at room temperature unless noted otherwise. 1. cryo-sections were air-dried for 45 minutes and then washed in PBS for 10 minutes 2. unspecific binding sites were blocked with M.O.M. blocking reagent (Vector Laboratories in 0.1% Tergitol in PBS for 60 minutes in a damp chamber 3. sections were washed 3 x 5 minutes each in PBS 4. sections were incubated with primary antibodies in M.O.M. diluent (Vector Laboratories overnight at 4 °C in a damp chamber ° rabbit anti-NeuN polyclonal antibody (Merck MIllipore, ABN78), 1:500 ° guinea pig anti-PSD95 monoclonal [Gp108E10] antibody (Synaptic Systems, 124308), 1:800 ° mouse anti-Synaptophysin monoclonal [SY38] antibody (Abcam, ab8049), 1:100 5. sections were washed 3 x 5 minutes each in PBS 6. sections were incubated with secondary antibodies in M.O.M. diluent (Vector Laboratories for 60 minutes in a damp chamber (light protected) ° donkey anti-rabbit IgG H+L Alexa Fluor 750-conjugated (abcam, ab175728), 1:500 ° donkey anti-guinea pig IgG H+L Cy3-conjugated (Jackson Immunoresearch, 706-165-148), 1:500 ° donkey anti-mouse IgG H+L DyLight 650-conjugated (Thermo Scientific, SA5-10169), 1:500 7. sections were washed 3 x 5 minutes each in PBS (light protected) 8. sections were incubated with DAPI working solution for 15 minutes (light protected) 9. sections were washed 2 x 5 minutes in PBS (light protected) 10. sections were washed for 5 minutes in ddH2O (light protected)11. sections were automatically covered with Mowiol and coverslips (light protected) using a Leica CV5030 coverslipper.

[0253] Imaging and Quantification: Whole slide scans of the stained sections were recorded on a Zeiss automatic microscope AxioScan Z1 with high aperture lenses, equipped with a Zeiss Axiocam 506 mono and a Hitachi 3CCD HV-F202SCL camera and Zeiss ZEN 3.7 software. Image analysis was done with Image Pro 10 (Media Cybernetics). At the beginning the target areas (cortex and subiculum) were identified by drawing regions of interest (ROI) on the images. Additional ROIs excluded wrinkles, air bubbles, or any other artifacts interfering with the measurement. Afterwards, signal of 6E10, Iba1, GFAP, CD68, PSD95, Synaptophysin, and NeuN were quantitatively evaluated within the identified areas. or quantification we used background correction if necessary and detected immunoreactive objects by adequate thresholding and morphological filtering (size, shape). Different object features were then quantified, among them the percentage of cumulative object area based on ROI size (immunoreactive area; this is the most comprehensive parameter indicating whether there are differences in immunoreactivity), the number of objects normalized to ROI size (object density), the mean signal intensity of identified objects (mean intensity; this indicates if there are differences in the cellular expression level of target proteins), and the size of above- threshold objects. Once the parameters of the targeted objects had been defined in a test run, the quantitative image analysis ran automatically so that the results were operator-independent and fully reproducible. Statistical analysis was performed using GraphPad Prism software.

[0254] No significant differences among any of the groups were observed in levels of Iba1, CD68, NeuN, Synaptophysin, or PSD95.

[0255] The embodiments of the disclosure described above are intended to be merely exemplary, numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.

Claims

1. CLAIMS 1. A method of treating or preventing a neurodegenerative disease, disorder, or condition, comprising administered to a subject an isoflavone agent and at least one additional agent, wherein the at least one additional agent increases microglial Aβ uptake and / or reduces pro- inflammatory cytokine production.

2. The method of claim 1, wherein the at least one additional agent increases microglial Aβ uptake.

3. The method of claim 1, wherein the at least one additional agent reduces pro- inflammatory cytokine production.

4. The method of any one of claims 1-3, further comprising administering one or more additional agents, wherein the one or more additional agents increase microglial Aβ uptake and / or reduces pro-inflammatory cytokine production.

5. The method of any one of claims 1-4, wherein the isoflavone agent is ipriflavone:or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1-5, wherein the at least one additional agent is selected from a urolithin, a steroid, a dihydropyridine, doxycycline, a doxycycline analog, a triazole antifungal compound, ziprasidone, ketanserin, dolutegravir, broxyquinoline, danthron, liothyronine, probucol, pergolide, clofazimine, enocitabine, and ufenamate, or a pharmaceutically acceptable salts, solvates, and / or hydrate thereof.

7. The method of any one of claims 1-4, wherein the at least one additional agent is selected from urolithin A, fluticasone propionate, doxycycline, albendazole, nifedipine, budesonide, nilotinib, ziprasidone, dolutegravir, or pharmaceutically acceptable salts, solvates, and / or hydrates thereof.

8. The method of any one of claims 1-6, wherein the at least one additional agent is represented by Formula II:Formula II or a pharmaceutically acceptable salt thereof, wherein R1is -H, -OH, or -OR4; R2is -H, -OH, -OR4, -NH2, -NHR4, -SH, -SR4, -F, -Cl, -Br, -CN, -OCN, -O(CH2)nNH2, - O(CH2)nCH3, -C1 to C10 alkyl, C3-C6 cycloalkyl, -C6 to C12 aryl, -SOCH3, -SO2, -ONO2, - NO2, and -N3; R3is -H, -OH, or -OR4; R4is a C1 to C10 alkyl; R5is -H or -OR4; and n is from 1 to 10, wherein each alkyl, cycloalkyl, and aryl of R2is optionally substituted with one or more substituents selected from halogen, C1 to C10 alkyl, C3 to C6 cycloalkyl, and C6 to C12 aryl.

9. The method of claim 8, wherein the at least one additional agent is urolithin A:or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-6, wherein the at least one additional agent is a steroid.

11. The method of claim 10, wherein the steroid is budesonide, mometasone furoate, alclometasone dipropionate, fluticasone propionate, flumethasone pivalate, or deoxycorticosterone acetate, or a pharmaceutically acceptable salt thereof.

12. The method of any one claims 1-6, wherein the at least one additional agent is a dihydropyridine.

13. The method of claim 12, wherein the dihydropyridine is a dihydropyridine Ca(II) channel blocker.

14. The method of claims 12 or 13, wherein the dihydropyridine is selected from nifedipine, nimodipine, isradipine, nilvadipine, amlodipine, benidipine, or barnidipine, or a pharmaceutically acceptable salt thereof.

15. The method of any one of claims 1-6, wherein the at least one additional agent is doxycycline, or a doxycycline analog, or a pharmaceutically acceptable salt and / or hydrate thereof.

16. The method of claim 15, wherein the at least one additional agent is doxycycline, or a doxycycline analog, or a pharmaceutically acceptable salt and / or hydrate thereof, selected from meclocycline and demeclocycline, doxycycline HCl, doxycycline hyclate, doxycyclate monohydrate, and demeclocycline HCl.

17. The method of any one of claims 1-6, wherein the at least one additional agent is a triazole antifungal compound.

18. The method of claim 17, wherein the at least one additional agent is a triazole antifungal compound selected from itraconazole and posaconazole.

19. The method of any one of claims 1-6, wherein the at least one additional agent is selected from: ketanserin, ziprasidone, dolutegravir, broxyquinoline, danthron, liothyronine,probucol, pergolide, clofazimine, enocitabine, and ufenamate, or a pharmaceutically acceptable salt and / or hydrate thereof.

20. The method of claim 19, wherein the at least one additional agent is selected from ketanserin tartrate hydrate, ziprasidone hydrochloride, ziprasidone hydrochloride hydrate, ziprasidone tartrate, dolutegravir, broxyquinoline, danthron, liothyronine, probucol, pergolide mesylate, clofazimine, enocitabine, and ufenamate.

21. The method of any one of claim 1-20, wherein the isoflavone agent is ipriflavone, and is administered to the subject in an amount that is from about 1 mg to about 1500 mg.

22. The method of any one of claims 1-5, 20, or 21, wherein the at least one additional agent is urolithin A, and is administered to the subject in an amount that is from about 0.5 mg to about 2500 mg.

23. The method of any one of claims 1-5, 20, or 21, wherein the at least one additional agent is dolutegravir, and is administered to the subject in an amount that is from about 25 mg to about 300 mg.

24. The method of any one of claims 1-5, 20, or 21, wherein the at least one additional agent is doxycycline, and is administered to the subject in an amount that is from about 100 mg to about 300 mg.

25. The method of any one of claims 1-5, 20, or 21, wherein the at least one additional agent is nifedipine, and is administered to the subject in an amount that is from about 50 mg to about 200 mg.

26. The method of any one of claims 1-5, 20, or 21, wherein the at least one additional agent is ziprasidone, and is administered to the subject in an amount that is from about 25 mg to about 300 mg.

27. The method of any one of claims 1-26, wherein the isoflavone agent is ipriflavone, and ipriflavone and the at least one additional agent are administered concurrently.

28. The method of any one of claims 1-26, wherein the isoflavone agent is ipriflavone, and ipriflavone and the at least one additional agent are administered separately.

29. The method of any one of claims 1-28, wherein the isoflavone agent is ipriflavone, and ipriflavone and the at least one additional agent are administered daily.

30. The method of any one of claims 1-29, wherein the isoflavone agent is ipriflavone, and ipriflavone and the at least one additional agent are administered once per day, twice per day, or three or more times per day.

31. The method of any one of claims 1-30, wherein the disease, disorder, or condition is selected from the group consisting of: Alzheimer’s disease, Parkinson’s disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, a polyglutamine expansion disorder, a trinucleotide repeat expansion disorder, Alexander disease, Alpe’s disease, ataxia telangiectasia, Batten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick’s disease, primary lateral sclerosis, Refsum’s disease, Sandhoff disease, Schilder’s disease, spinal cord injury, spinal muscular atrophy, Steele Richardson-Olszewski disease, and Tabes dorsalis.

32. A combination comprising an isoflavone agent and at least one additional agent, wherein the at least one additional agent is selected from: a urolithin, a flavonoid, a steroid, a dihydropyridine, doxycycline, a doxycycline analog, a triazole antifungal compound, cat’s claw, nicotinamide riboside, ziprasidone, ketanserin, dolutegravir, broxyquinoline, danthron, liothyronine, probucol, pergolide, clofazimine, enocitabine, and ufenamate, or pharmaceutically acceptable salts, solvates, and / or hydrates thereof.

33. The combination of claim 32, wherein the isoflavone agent is ipriflavone:or a pharmaceutically acceptable salt thereof.

34. The combination of claims 32 or 33, wherein the at least one additional agent is selected from urolithin A, fluticasone propionate, doxycycline, albendazole, nifedipine, budesonide, nilotinib, ziprasidone, dolutegravir, or pharmaceutically acceptable salts, solvates, and / or hydrates thereof.

35. The combination of any one of claims 32-34, wherein the at least one additional agent is represented by Formula II:Formula II or a pharmaceutically acceptable salt thereof, wherein R1is -H, -OH, or -OR4; R2is -H, -OH, -OR4, -NH2, -NHR4, -SH, -SR4, -F, -Cl, -Br, -CN, -OCN, -O(CH2)nNH2, - O(CH2)nCH3, -C1 to C10 alkyl, C3-C6 cycloalkyl, -C6 to C12 aryl, -SOCH3, -SO2, -ONO2, -NO2, and -N3; R3is -H, -OH, or -OR4; R4is a C1to C10alkyl; R5is -H or -OR4; and n is from 1 to 10, wherein each alkyl, cycloalkyl, and aryl of R2is optionally substituted with one or more substituents selected from halogen, C1 to C10 alkyl, C3 to C6 cycloalkyl, and C6 to C12 aryl.

36. The combination of claim 35, wherein the at least one additional agent is urolithin A:or a pharmaceutically acceptable salt thereof.

37. The combination of claims 32 or 33, wherein the at least one additional agent is a steroid.

38. The combination of claim 37, wherein the steroid is budesonide, mometasone furoate, alclometasone dipropionate, fluticasone propionate, flumethasone pivalate, or deoxycorticosterone acetate, or a pharmaceutically acceptable salt thereof.

39. The combination of claims 32 or 33, wherein the at least one additional agent is a dihydropyridine.

40. The combination of claim 39, wherein the dihydropyridine is a dihydropyridine Ca(II) channel blocker.

41. The combination of claims 39 or 40, wherein the dihydropyridine is selected from nifedipine, nimodipine, isradipine, nilvadipine, amlodipine, benidipine, or barnidipine, or a pharmaceutically acceptable salt thereof.

42. The combination of claims 32 or 33, wherein the at least one additional agent is doxycycline, or a doxycycline analog, or a pharmaceutically acceptable salt and / or hydrate thereof.

43. The combination of claim 42, wherein the at least one additional agent is doxycycline, or a doxycycline analog, or a pharmaceutically acceptable salt and / or hydrate thereof, selected from meclocycline and demeclocycline, doxycycline HCl, doxycycline hyclate, doxycyclate monohydrate, and demeclocycline HCl.

44. The combination of claims 32 or 33, wherein the at least one additional agent is a triazole antifungal compound.

45. The combination of claim 44, wherein the at least one additional agent is a triazole antifungal compound selected from itraconazole and posaconazole.

46. The combination claims 32 or 33, wherein the at least one additional agent is selected from: ketanserin, ziprasidone, dolutegravir, broxyquinoline, danthron, liothyronine, probucol, pergolide, clofazimine, enocitabine, and ufenamate, or a pharmaceutically acceptable salt and / or hydrate thereof.

47. The combination of claim 46, wherein the at least one additional agent is selected from ketanserin tartrate hydrate, ziprasidone hydrochloride, ziprasidone hydrochloride hydrate, ziprasidone tartrate, dolutegravir, broxyquinoline, danthron, liothyronine, probucol, pergolide mesylate, clofazimine, enocitabine, and ufenamate.

48. A kit comprising the combination of any one of claims 32-47.

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