ATP6v1b2 binding agents and uses thereof

Abstract

More particularly, the invention relates to a binding agent capable of binding ATP6V1B2 and / or a functionally active fragment thereof, and to the use of said binding agent for the preparation of an agent for improving learning ability, treating cognitive disorders, and / or treating neurodegenerative diseases.

Description

ATP6V1B2 binders and uses thereof Technical Field The present application relates to the field of biomedicine, and specifically to an ATP6V1B2 binder and its use in the treatment of neurodegenerative diseases. Background Art Alzheimer's disease (AD) is generally caused by synaptic and neuronal damage, and abnormalities in the structure and function of neural circuits. Since the mechanisms of synaptic and neuronal damage are still unclear, effective prevention and treatment methods for AD have been developed very slowly. The ATP6V1B2 protein encoded by the ATP6V1B2 gene is an important structural protein of the proton pump driven by ATP hydrolysis. It is widely distributed in human tissues, but is more abundant in brain tissue, kidneys, osteoclasts and other parts. It plays an important role in synaptic transmission and lysosomal acidification. Its gene mutation can lead to DOORS syndrome (susceptible autosomal dominant congenital deafness with nail dysplasia syndrome). Reduced expression of ATP6V1B2 protein may be related to the onset of AD. Summary of the invention The present application provides a method for improving a subject's learning ability. The present application finds that a binder of ATP6V1B2 can be used as a potential drug for improving a subject's learning ability. In one aspect, the present application provides a binding agent that binds to ATP6V1B2 and / or a functionally active fragment thereof. In certain embodiments of the binding agent, the ATP6V1B2 and / or its functionally active fragment is derived from a mammal. In certain embodiments of the binding agent, the ATP6V1B2 or a functionally active fragment thereof is derived from human or mouse. In certain embodiments of the binding agent, the ATP6V1B2 comprises the amino acid sequence shown in SEQ ID NO: 8 or 16. In certain embodiments of the binding agent, the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:5. In certain embodiments of the binding agent, the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO.5. In certain embodiments of the binding agent, the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the human ATP6V1B2 protein. In certain embodiments of the binding agent, the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the mouse ATP6V1B2 protein. In certain embodiments of the binding agent, the functionally active fragment of ATP6V1B2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 10-11. In certain embodiments of the binding agent, the ATP6V1B2 comprises an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO. 9 or 17. In certain embodiments, the binding agent is capable of modulating proton pump activity and / or function. In certain embodiments, the binding agent is capable of increasing the expression level and / or activity of a proton pump-related protein in a subject. In certain embodiments of the binding agent, the expression level of the proton pump associated protein is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. In certain embodiments of the binding agent, the expression level of the proton pump-associated protein is measured by utilizing a substance selected from the following group: a primer capable of specifically amplifying a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a proton pump-associated protein, a small molecule that specifically binds to a proton pump-associated protein, a probe that specifically binds to a proton pump-associated protein, and a polypeptide that specifically binds to a proton pump-associated protein. In certain embodiments, the binding agent is capable of modulating the expression level and / or activity of ATP6V1B2. In certain embodiments, the binding agent is capable of increasing the expression level and / or activity of ATP6V1B2 in a subject. In the binding agent of certain embodiments, the expression level of ATP6V1B2 includes the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein. In certain embodiments of the binding agent, wherein the increase comprises an increase in the expression level and / or activity of the ATP6V1B2 by at least about 10% compared to the expression level and / or activity of native ATP6V1B2 in the subject. In certain embodiments of the binding agent, the expression level of ATP6V1B2 is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry. In certain embodiments of the binding agent, the expression level of ATP6V1B2 is measured by utilizing a substance selected from the group consisting of: primers capable of specifically amplifying the ATP6V1B2 gene, nucleic acid molecules that specifically bind to the ATP6V1B2 gene, nucleic acid molecules that specifically bind to the ATP6V1B2 protein, small molecules that specifically bind to the ATP6V1B2 protein, probes that specifically bind to the ATP6V1B2 protein, and polypeptides that specifically bind to the ATP6V1B2 protein. In certain embodiments, the binding agent is capable of increasing neuronal synaptic transmitter release. In certain embodiments of the binding agent, wherein said increase comprises an increase of at least about 10% compared to the level of synaptic transmitter release in native neurons in said subject. In certain embodiments, the binding agent increases the firing frequency of excitatory postsynaptic currents. In certain embodiments of the binding agent, wherein said increase comprises an increase of at least about 10% compared to the level of original firing frequency of excitatory postsynaptic current in said subject. In certain embodiments, the binding agent comprises a protein and / or a polypeptide. In certain embodiments, the binding agent comprises the amino acid sequence shown in SEQ ID NO: 33 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the binding agent comprises an amino acid sequence as shown in any one of SEQ ID NOs: 30-32 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the binding agent comprises an amino acid sequence as shown in any one of SEQ ID NOs: 27-29 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the binding agent comprises the amino acid sequence shown in SEQ ID NO: 19-26 and / or variants thereof. In certain embodiments, the binding agent comprises a multimer. In certain embodiments of the binding agent, the multimer comprises a homodimer. In certain embodiments of the binding agent, the cysteine ​​in its amino acid sequence does not have a thiol-blocking modification. In certain embodiments of the binding agent, the serine in its amino acid sequence does not have a phosphorylation modification. In certain embodiments, the binding agent comprises a fusion protein and / or a fusion polypeptide. In certain embodiments of the binding agent, the fusion protein and / or fusion polypeptide comprises a molecule capable of being transported across the blood-brain barrier to the brain. In certain embodiments of the binding agent, the molecule capable of being transported across the blood-brain barrier to the brain comprises a polypeptide. In certain embodiments of the binding agent, the molecule capable of being transported across the blood-brain barrier to the brain comprises a penetrant peptide. In certain embodiments of the binding agent, the cell-penetrating peptide comprises the amino acid sequence as set forth in SEQ ID NO:34. In certain embodiments, the binding agent comprises the amino acid sequence as shown in SEQ ID NO: 48, wherein X is any amino acid. In certain embodiments, the binding agent comprises an amino acid sequence as shown in any one of SEQ ID NOs: 45-47, wherein X is any amino acid. In certain embodiments, the binding agent comprises an amino acid sequence as shown in any one of SEQ ID NOs: 42-44 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the binding agent comprises an amino acid sequence as shown in any one of SEQ ID NOs: 35-41 and / or variants thereof. In another aspect, the present application provides an isolated polypeptide comprising an amino acid sequence as shown in SEQ ID NO: 33 and / or a variant thereof, wherein X is any amino acid. In certain embodiments, the polypeptide comprises the amino acid sequence shown in SEQ ID NO: 30-32 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the polypeptide comprises an amino acid sequence shown in any one of SEQ ID NOs: 27-29 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the polypeptide comprises the amino acid sequence shown in SEQ ID NO: 19-26 and / or variants thereof. On the other hand, the present application provides a fusion polypeptide comprising the polypeptide described in the present application. In certain embodiments, the fusion polypeptide further comprises a molecule capable of being transported across the blood-brain barrier to the brain. In certain embodiments of the fusion polypeptide, the molecule transported across the blood-brain barrier to the brain comprises a polypeptide. In certain embodiments of the fusion polypeptide, the molecule capable of being transported across the blood-brain barrier to the brain comprises a cell-penetrating peptide. In certain embodiments of the fusion polypeptide, the cell-penetrating peptide comprises the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof. In certain embodiments, the fusion polypeptide comprises the amino acid sequence as shown in SEQ ID NO: 48 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the fusion polypeptide comprises an amino acid sequence as described in any one of SEQ ID NOs: 45-47 and / or variants thereof, wherein X is any amino acid. In certain embodiments, the fusion polypeptide comprises an amino acid sequence as described in any one of SEQ ID NOs: 42-44 and / or a variant thereof, wherein X is any amino acid In certain embodiments, the fusion polypeptide comprises an amino acid sequence as described in any one of SEQ ID NOs: 35-41 and / or variants thereof. In another aspect, the present application provides an immunoconjugate comprising the binding agent described herein, the polypeptide described herein and / or the fusion polypeptide described herein. On the other hand, the present application provides a nucleic acid molecule encoding the binding agent described in the present application, the polypeptide or variant thereof described in the present application and / or the fusion polypeptide described in the present application. In another aspect, the present application provides a vector comprising the nucleic acid molecule described in the present application. On the other hand, the present application provides a cell comprising the binding agent described in the present application, the polypeptide or variant thereof described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application and / or the vector described in the present application. On the other hand, the present application provides a pharmaceutical combination comprising the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein. On the other hand, the present application provides a pharmaceutical composition comprising the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein, and optionally a pharmaceutically acceptable carrier. On the other hand, the present application provides a kit comprising the binding agent described in the present application, the polypeptide described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the drug combination described in the present application and / or the pharmaceutical composition described in the present application. On the other hand, the present application provides a use of the binding agent described in the present application, the polypeptide described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the drug combination described in the present application and / or the pharmaceutical composition described in the present application in the preparation of a kit. On the other hand, the present application provides a binding agent described in the present application, a polypeptide described in the present application, a fusion polypeptide described in the present application, an immunoconjugate described in the present application, a nucleic acid molecule described in the present application, a vector described in the present application, a cell described in the present application, a drug combination described in the present application and / or a pharmaceutical composition described in the present application, for use in detecting ATP6V1B2. On the other hand, the present application provides a method for detecting ATP6V1B2 in a sample, which comprises administering the binding agent described in the present application, the polypeptide described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the drug combination described in the present application, the pharmaceutical composition described in the present application and / or the kit described in the present application. On the other hand, the present application provides a use of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in the preparation of an agent for improving learning ability, treating cognitive disorders and / or treating neurodegenerative diseases. In certain embodiments, the learning ability comprises cognitive ability, motor ability, memory ability and / or spatial exploration ability. In certain embodiments, the improvement in learning ability comprises an improvement in the subject's learning ability assessment score by at least about 50% compared to the subject's original learning ability assessment score. In certain embodiments, the assessment score of learning ability is measured by performing a test selected from the group consisting of a novel object recognition test and a water maze test. In certain embodiments, the novel object recognition test evaluates the cognitive ability, motor ability and / or spatial exploration ability. In certain embodiments, the water maze test evaluates the memory ability, motor ability and / or spatial exploration ability. In certain embodiments, the cognitive impairment comprises mild cognitive impairment (MCI), moderate cognitive impairment and severe cognitive impairment. In certain embodiments, the cognitive impairment comprises cognitive impairment caused by normal aging, Lewis body dementia (LBD), frontotemporal dementia and / or vascular dementia. In certain embodiments, the cognitive impairment inducing diseases include Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). In certain embodiments, the neurodegenerative disease comprises an acute neurodegenerative disease and a chronic neurodegenerative disease. In certain embodiments, the neurodegenerative disease includes a neurodegenerative disease caused by neuronal death and glial cell homeostasis, a neurodegenerative disease caused by aging, a neurodegenerative disease caused by affected CNS cell function, a neurodegenerative disease caused by abnormal intercellular communication and / or a neurodegenerative disease caused by impaired cell motility. In certain embodiments, the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD). In certain embodiments, the subject comprises a mammal. In certain embodiments, the subject comprises a human. In certain embodiments, the subject comprises a non-cognitive disorder patient and / or a non-neurodegenerative disease patient. In certain embodiments, the subject comprises a patient with a neurodegenerative disease and / or a patient with a cognitive disorder. In certain embodiments, the subject comprises an Alzheimer's disease patient. In certain embodiments, the subject is elderly. In certain embodiments, the agent is formulated for oral administration and / or injection. In certain embodiments, the agent is formulated for intravenous injection. On the other hand, the present application provides a binding agent described herein, a polypeptide described herein, a fusion polypeptide described herein, an immunoconjugate described herein, a nucleic acid molecule described herein, a vector described herein, a cell described herein, a drug combination described herein and / or a pharmaceutical composition described herein for use in improving learning ability, treating cognitive disorders and / or treating neurodegenerative diseases. On the other hand, the present application provides a method for improving learning ability, treating cognitive impairment and / or treating neurodegenerative diseases. A method comprising administering to a subject in need thereof the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein. Those skilled in the art can easily perceive other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of the present application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which the present application relates. Accordingly, the description in the drawings and specification of the present application is merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS The specific features of the invention involved in this application are shown in the attached claims. The features and advantages of the invention involved in this application can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows: FIG. 1A-FIG 1B show that the polypeptides and variants described in the present application can bind to the ATP6V1B2 protein. FIG2 shows that the polypeptides described in the present application significantly enhance the frequency of sEPSC, but have no significant effect on the amplitude of sEPSC. DETAILED DESCRIPTION The following is an explanation of the implementation of the present invention by means of specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Definition of terms In this application, the term "binding agent" generally refers to a natural molecule or non-natural molecule that specifically binds to a target or a portion of a target. Binding agents can include small molecule compounds, polymers and / or biomacromolecules. Binding agents can include proteins, peptides, nucleic acids, sugars, lipids and small molecule compounds. For example, a binding agent can include a polypeptide. For example, a binding agent can include a fusion polypeptide. In this application, the term "ATP6V1B2" generally refers to ATPase H + ATPase H+ transporting V1 subunit B2 protein (or ATP6B2, DOOD, HO57, VATB, VPP3, Vma2 or ZLS2), and a gene encoding the protein. The ATP6V1B2 can be a protein that mediates acidification of organelles in eukaryotic cells. Multi-subunit enzyme. The ATP6V1B2 can participate in processes such as protein sorting, zymogen activation, receptor-mediated endocytosis and synaptic vesicle proton gradient generation. The ATP6V1B2 protein can include a cytoplasmic V1 domain and a transmembrane V0 domain. The accession number of human ATP6V1B2 in GenBank is 526. The accession number of human ATP6V1B2 in UniProt can be P21281. In this application, the term "proton pump-related protein" generally refers to a protein encoding and / or expressing a proton pump. The proton pump may be a protein that actively transports hydrogen ions against the electrochemical potential difference of hydrogen ions on both sides of the biological membrane. The proton pump may include a Na-K pump, a Ca- 2+ Pump, H + -ATP pump and H + Pyrophosphate pump. In the present application, the term "expression level" generally refers to the protein, RNA or mRNA level of a specific related gene. Any method known in the art can be used to measure the expression level of a specific related gene (e.g., human ATP6V1B2 gene). In the present application, "expression" generally refers to the process by which the information encoded by a gene is converted into a structure present in a cell and operated in a cell. For example, reverse transcription and amplification analysis (e.g., PCR, connection RT-PCR or quantitative RT-PCR), hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, protein blotting, immunohistochemistry, immunostaining or mass spectrometry can be included. Analysis can be performed directly on a biological sample or on the protein / nucleic acid separated from the sample. In this application, the term "activity" generally refers to any activity associated with a particular protein. In this application, the activity may include, for example, any activity associated with the ATP6V1B2 protein. The activity may include an enzymatic activity associated with a protease. In some cases, the activity may include a biological activity. In some cases, the activity may include binding of a protein to a receptor, for example, the binding may produce a measurable downstream effect. In this application, the activity may include any activity that would be attributed to the protein by a person skilled in the art. In the present application, the term "variant" generally refers to a polypeptide comprising an amino acid sequence that differs from the amino acid sequence of a parent or reference polypeptide (e.g., a wild-type polypeptide) by at least one amino acid residue. In the present application, the variant may have a higher (e.g., at least 80%) homology with the parent or reference polypeptide. The homology may include sequence similarity or identity. In the present application, the homology may be determined using standard techniques known in the art (see, e.g., Smith and Waterman, Adv. Appl. Math. Advances in Applied Mathematics); the percentage of identity shared by polynucleotide or polypeptide sequences is determined by direct comparison of sequence information between molecules, the comparison being performed by sequence alignment and using methods known in the art to determine identity. An example of an algorithm suitable for determining sequence similarity is the BLAST algorithm (see Altschul et al., J. Mol. Biol. Journal of Molecular Biology, 215: 403-410).

[1990] ). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (NCBI). In the present application, the “variant” and / or “functional variant” may be, for example, a substitution, deletion or addition of a single amino acid sequence in the amino acid sequence of the protein and / or the polypeptide (e.g., a binding agent that binds to ATP6V1B2 or a fragment thereof). or more amino acids. For example, the variant may comprise a protein or polypeptide having an amino acid change by at least 1, such as 1-30, 1-20 or 1-10, and for example 1, 2, 3, 4 or 5 amino acid substitutions, deletions and / or insertions. The functional variant may substantially maintain the biological properties of the protein or polypeptide before the change (e.g., substitution, deletion or addition). For example, the functional variant may maintain at least 60%, 70%, 80%, 90%, or 100% of the biological activity (e.g., the ability to bind to ATP6V1B2) of the protein or polypeptide before the change. For example, the substitution may be a conservative substitution. For example, the variant may also be a polypeptide covering its functionally active fragments, not limited to a polypeptide comprising a functionally active fragment of the protein produced after processing and / or modification occurring in a cell. In the present application, the "variant" may be a homologue. The homologue may be a protein or polypeptide having at least about 85% (e.g., at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology with the amino acid sequence of the protein and / or the polypeptide (e.g., a binding agent that specifically binds to ATP6V1B2 or a fragment thereof). In the present application, described homology generally refers to the similarity, similarity or association between two or more sequences.Can calculate " sequence homology percentage ratio " in the following manner: two sequences to be compared are compared in a comparison window, determine that there is identical nucleic acid base (for example, A, T, C, G, U) or identical amino acid residue (for example, Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) number of position to obtain the number of matching positions, the number of matching positions is divided by the total number of positions (that is, window size) in the comparison window, and the result is multiplied by 100, to produce sequence homology percentage ratio.Comparison carried out in order to determine the sequence homology percentage ratio, can realize in various ways known in the art, for example, use publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximum alignment over the full length of the sequences being compared or within a region of the sequence of interest. The homology can also be determined by the following methods: FASTA and BLAST. A description of the FASTA algorithm can be found in W. R. Earson and DJ. Lipman, "Improved tools for biological sequence comparisons," Proc. Natl. Acad. Sci., 85: 2444-2448, 1988; and DJ. Lipman and W. R. Earson, "Rapid and sensitive protein similarity searches," Science, 227: 1435-1441, 1989. A description of the BLAST algorithm can be found in S. Altschul, W. Gish, W. Miller, E. W. Myers and D. Lipman, "A basic local alignment search tool," Journal of Molecular Biology, 215: 403-410, 1990. In this application, the term "amino acid" generally refers to naturally occurring, synthetic, or unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function in a similar manner to the naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs with variant side chains, and stereoisomers of any of the foregoing. The 20 commonly used amino acids and their abbreviations used in this application are in conventional usage. See Immunology-A Synthesis (2nd edition, ES Golub and DR Gren, eds., Sinauer Associates, Sunderland, Mass. (1991)), the contents of which are incorporated herein by reference. This application uses commonly used amino acid single-letter abbreviations and three-letter abbreviations (Bruce Alberts et al., Molecular Biology of the Cell, Garland Publishing, Inc., New York (4th edition, 2002)). In the present application, the term "conservative replacement or conservative substitution" is also called "conservative mutation", which generally refers to the substitution of an amino acid with other amino acids having similar properties (e.g., charge, side chain size, hydrophobicity / hydrophilicity, main chain conformation, and rigidity, etc.) in a protein. Examples of amino acid groups having side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxy side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine ​​and methionine. Conservative amino acid substitution groups can be, for example, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. In this application, the term "non-conservative substitution" is also called "radical replacement (Radical Replacement or Radical Substitution)", which generally refers to the substitution of amino acids with other amino acids having different properties in proteins (such as charge, side chain size, hydrophobicity / hydrophilicity, main chain conformation and rigidity, etc.). For example, non-conservative substitutions can also involve the use of non-natural amino acids. In the present application, the term "polar amino acid" may include polar uncharged amino acids, basic (positively charged) amino acids, acidic (negatively charged) amino acids. For example, polar amino acids may include threonine, serine, cystine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid. In the present application, the term "non-polar amino acids" may include phenylalanine, proline, valine, leucine, isoleucine, methionine, tryptophan, alanine, glycine. In the present application, the term "fusion polypeptide" generally refers to a polypeptide that comprises at least two discrete peptides or polypeptides (which do not exist together in this way in natural polypeptides, that is, these parts do not exist naturally in the same polypeptide or in the same order), or is composed of at least two discrete peptides or polypeptides (which do not exist together in this way in natural polypeptides, that is, these parts do not exist naturally in the same polypeptide or in the same order). The discrete peptides or polypeptides can be directly or indirectly connected together to form a fusion polypeptide. For example, the discrete peptides or polypeptides can be connected by peptide bonds to form a fusion polypeptide. For example, the discrete peptides or polypeptides can be connected by a linker to form a fusion polypeptide. For example, the fusion polypeptide described in the present application may include a fusion polypeptide formed by connecting a polypeptide capable of binding to ATP6V1B2 and a polypeptide having a specific function. In the present application, the term "fusion protein" generally refers to a protein composed of two or more polypeptides. In the present application, the term "blood-brain barrier (BBB)" generally refers to the physiological barrier between peripheral circulation and the brain and spinal cord, which is composed of the end feet of brain capillary endothelial cells, basement membranes and glial cells, forming a tight barrier that restricts molecules, even very small molecules (such as urea (60 daltons)) transported to the brain. The BBB in the brain, the blood-spinal cord barrier in the spinal cord and the blood-retinal barrier in the retina are continuous capillary barriers in the CNS, and are collectively referred to as blood-brain barrier or BBB in this article. BBB also encompasses blood-CSF barrier (choroid plexus), wherein the barrier is composed of ependymal cells rather than capillary endothelial cells. In this application, the term "penetrating peptide" generally refers to a class of short peptides that can pass through cell membranes or tissue barriers. For example, penetrating peptides can carry biological macromolecules such as proteins, RNA, and DNA into cells through mechanisms such as endocytosis and direct penetration to exert their effector functions. In the present application, the term "polymer" generally refers to a molecule having two or more polypeptide chains associated by covalent, non-covalent, or both covalent and non-covalent interactions. The polymer may include a dimer. In the present application, the term "homodimer" generally refers to a molecule formed by two identical monomers. The two identical monomers can aggregate, complex or associate with each other through covalent and / or non-covalent interactions. In the present application, the term "sulfhydryl blocking" generally refers to blocking free sulfhydryl groups to make it difficult to form intramolecular and / or intermolecular disulfide bonds. In the present application, the sulfhydryl blocking can occur on cysteine ​​residues. The sulfhydryl blocking can prevent the formation of disulfide bonds between cysteine ​​residues of proteins and prevent the proteins from being cross-linked or modified. The sulfhydryl blocking can be achieved by using a blocking agent, which can be a reducing agent. The blocking agent can include dithiothreitol (DTT), β-mercaptoethanol (BME) and tris(2-carboxyethyl)phosphine hydrochloride (TCEP·HCl). In the present application, the term "serine phosphorylation" generally refers to phosphorylation modification occurring on serine residues. The serine phosphorylation can be a process in which a phosphate group of a donor (e.g., ATP or GTP) is transferred to a serine residue. The serine phosphorylation can be assisted by protein kinases. The serine phosphorylation can result in changes in protein activity. In this application, the term "isolated" generally refers to an artificially obtained substance from a natural state. For example, a certain polynucleotide or polypeptide that is not isolated naturally exists in a living animal, and the same polynucleotide or polypeptide with high purity isolated from this natural state can be called isolated. The term "isolated" may not exclude the presence of artificial or synthetic substances, nor may it exclude the presence of other impure substances that do not affect the activity of the substance. In this application, the term "nucleic acid molecule" generally refers to nucleotides of any length in isolated form, either deoxyribonucleotides or ribonucleotides, or analogs isolated from their natural environment or artificially synthesized. In this application, the term "vector" generally refers to a nucleic acid carrier into which a polynucleotide encoding a protein can be inserted and the protein can be expressed. A vector can transform, transduce or transfect host cells so that the genetic material elements it carries are expressed in the host cells. A vector may contain multiple elements that control expression. In addition, a vector may also It may contain a replication origin site. The vector may also include components that assist it in entering the cell. In the present application, the term "cell" generally refers to a single cell, cell line or cell culture that may be or has been a recipient of a subject's plasmid or vector, including a nucleic acid molecule described herein or a vector described herein. A cell may include the offspring of a single cell. Due to natural, accidental or intentional mutations, the offspring may not necessarily be identical to the original parent cell (in the form of the total DNA complement or in the genome). A cell may include a cell transfected in vitro with a vector described herein. In the present application, the term "immunoconjugate" generally refers to a substance formed by linking a polypeptide with other active agents, which may be small molecule active agents, such as therapeutic agents, imaging probes or spectroscopy probes. In the present application, the term "pharmaceutical composition" generally refers to a composition for preventing / treating a disease or condition. The pharmaceutical composition may include an isolated polypeptide as described herein, a nucleic acid molecule as described herein, a vector as described herein, and / or a cell as described herein, and optionally a pharmaceutically acceptable adjuvant. In addition, the pharmaceutical composition may also include suitable formulations such as one or more (pharmaceutically effective) carriers. The acceptable ingredients of the composition may be non-toxic to the recipient at the dosage and concentration used. The pharmaceutical composition of the present application includes, but is not limited to, liquid, frozen and lyophilized compositions. In this application, the term "pharmaceutically acceptable carrier" generally refers to a pharmaceutically acceptable carrier, excipient or stabilizer that is non-toxic to cells or mammals exposed thereto at the doses and concentrations employed. Physiologically acceptable carriers may include suitable substances. Pharmaceutically acceptable carriers are generally not the same substance as vectors used to insert nucleic acids in genetic engineering. In this application, the term "specific binding" or "specific" generally refers to a measurable and reproducible interaction, such as binding between a target and an antibody, which can determine the presence of a target in the presence of a heterogeneous population of molecules (including biomolecules). For example, an antibody that specifically binds to a target (which may be an epitope) may be an antibody that binds to the target with greater affinity, avidity, more readily, and / or for a greater duration than it binds to other targets. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among proteins of different species. In certain embodiments, specific binding may include but does not require exclusive binding. In the present application, the term "transmitter release" generally refers to neurotransmitter release, that is, a neuron releases a neurotransmitter (Neurotransmitter) encapsulated in a vesicle into the synaptic cleft, which acts on another neuron to transmit information. In the transmitter release process, the basic structure of the neural circuit, the synapse (Synapse), may be involved. In some cases, the transmitter release may be referred to as synaptic transmission (Synaptic transmission). The method of transmitter release may include synchronous release (Synchronous release), asynchronous release (Asynchronous release) and spontaneous release (Spontaneous release). In this application, the term "firing frequency" generally refers to the firing frequency of action potentials. The process of rapid and reversible inversion and recovery of the potential on both sides of the membrane generated on the basis of the resting potential when the excitatory cell is stimulated. The action potential can be composed of a peak potential and an afterpotential, corresponding to the depolarization (Depolarisation) and hyperpolarization (Hyperpolarization) processes respectively. The discharge of action potentials can have the characteristics of pulses. In some cases, the frequency of pulse discharge is the ratio of the number of pulse discharges to the time. For example, the discharge frequency may include the discharge frequency of synaptic vesicles releasing neurotransmitters. For example, the discharge frequency may include the discharge frequency of excitatory postsynaptic currents. In this application, in this application, the term "neuron" generally refers to a nerve cell, which is the main functional unit of the nervous system. A neuron can be composed of a cell body and its protrusions, an axon, and one or more dendrites. A neuron can transmit information to other neurons or cells by releasing neurotransmitters at synapses. In this application, the term "learning ability" generally refers to all abilities related to or required for the learning / cognitive process. The learning ability may include the ability to acquire new information, knowledge and / or skills through a process including experience, learning or training. The learning ability may include imagination, attention, perceptual observation ability, reading ability, analytical ability, operational ability, adaptability, inductive and concluding ability, problem-solving ability or a combination thereof. In this application, the term "cognitive ability" generally refers to the ability to process information through perception. The cognitive ability may include the ability to grasp the composition of things, the relationship between performance and other things, the driving force of development, the direction of development, and the basic laws. In this application, the term "athletic ability" generally refers to the ability to participate in sports and training. The athletic ability may include aerobic exercise capacity, muscle strength, body flexibility, balance ability and reaction ability. The athletic ability may be a comprehensive expression of multiple factors such as physical shape, quality, skills, skills and psychological ability. In this application, the term "memory ability" generally refers to the ability to recognize, retain, re-recognize and reproduce the content and experience reflected by objective things. The memory ability may include sensory memory ability, short-term memory ability and long-term memory ability. In this application, the term "spatial exploration ability" generally refers to the ability to explore the shape and / or position of an object. The spatial exploration ability includes observing, thinking, imagining, recognizing and / or exploring the shape and / or position of an object. In the present application, the term "assessment score of learning ability" generally refers to a quantitative measurement score of a subject's learning ability. The assessment score of the learning ability can be obtained by conducting an assessment including attention / executive function (e.g., Wechsler memory test), language ability assessment (e.g., language screening test (the language screening test, LAST)), visual space and structural ability assessment (e.g., visual motor integration test, Hooper visual organization test, object patchwork test, graphic arrangement test, clock drawing test), application ability assessment, daily function assessment (e.g., disability assessment for dementia (DAD)) and / or neuropsychological scales. In some cases, the assessment score of the learning ability can be obtained by conducting a mini-mental state examination (mini-mental state examination, MMSE), Montreal cognitive assessment scale (Montreal cognitive assessment, MoCA), Alzheimer's disease assessment scale-cognitive part (Alzheimer disease assessment scale-cog, ADAS-cog) and clinical dementia rating scale (clinical dementia rating scale, CDR) The score obtained by testing is obtained. In the present application, the term "novel object recognition test" generally refers to a test for detecting the time required for animals to learn to recognize new objects by making animals (e.g., mice) recognize objects in a specific space. In some cases, the novel object recognition test can refer to the test method described in Ennaceur et al., Behav Brain Res 80 9-25, 1996. For example, the novel object recognition test may include the following steps: two identical objects are placed in a container of fixed volume, mice are placed in the container to recognize the two objects, and after a period of time, one of the two objects in the same container is replaced with a new object with a different shape, and then the search time of the mice for the new object is measured. In the present application, the term "water maze test" generally refers to a test in which an animal (e.g., a mouse) is forced to swim, thereby learning to find a platform hidden in the water. The water maze test (e.g., Morris water maze) can test the learning ability and / or memory ability of mice to a sense of spatial position and direction. The water maze test may also include acquired training, exploratory training, alignment training, or alignment exploratory training. If the time required for an animal (e.g., a mouse) to find a platform from entering the water is shorter, and the distance moved during this period is approximately shorter, then the assessment score of the learning ability of the animal (e.g., a mouse) is correspondingly approximately high. The water maze evaluation test can be an important experiment for evaluating learning ability. In the present application, the term "neurodegenerative disease" generally refers to cognitive disorders such as dementia caused by the gradual loss of neuronal structure and function, including neuronal death and glial cell imbalance. In some cases, age (e.g., Alzheimer's disease (AD), Parkinson's disease (PD)) or gene mutations that affect CNS cell function (e.g., Huntington's disease, early-onset AD or PD, amyotrophic lateral sclerosis (ALS)) can cause the neurodegenerative disease. The neurodegenerative disease may have changes and / or conditions selected from the following: protein misfolding and aggregation; neuroinflammation (e.g., CNS inflammation that occurs under toxic stimulation (e.g., protein aggregation), infection, traumatic injury, or autoimmune signal stimulation); changes in cell signal transduction; acquired aging / cell death (e.g., interrupted apoptotic signal transduction, mitochondrial dysfunction, impaired autophagy, and necrotic bodies activated by stress / inflammation); motor cell damage and epigenetic changes. In this application, the term "Alzheimer's disease" generally refers to precocious dementia, senile dementia, a neurodegenerative disease with a slow progression of disease that worsens over time. The most common early symptom is loss of short-term memory (difficulty remembering recent events). As the disease progresses, at least one of the following symptoms may gradually appear: language disorders, disorientation (e.g., easy to get lost), emotional instability, loss of motivation, inability to take care of oneself, and behavioral problems. The true cause of Alzheimer's disease is still unknown, and its progression may be related to the deposition of amyloid plaques in the brain and the fibrillary tangles caused by hyperphosphorylation of Tau proteins. There is currently no treatment that can stop or reverse the course of the disease, and only a few methods may temporarily relieve or improve symptoms. In this application, the terms "early cognitive impairment (MCI)" and "mild cognitive impairment" are used interchangeably and generally refer to an intermediate clinical state between normal cognition and cognitive impairment. The MCI may include cognitive impairment that meets the criteria for dementia but exceeds normal aging. MCI is diverse in clinical manifestations, etiology, prognosis and prevalence. In some cases, MCI may be a pathological stage of Alzheimer's disease. Certain forms of cognitive impairment may be considered as early manifestations of neurodegenerative diseases, which will eventually lead to dementia. In this application, the terms "mid-term cognitive impairment" and "moderate cognitive impairment" may be used interchangeably, and may include more severe memory impairment, affecting the patient's ability to live independently, and / or may be accompanied by sphincter disorders. In this application, the terms "late cognitive impairment" and "severe cognitive impairment" may be used interchangeably, and may include severe intellectual impairment, inability to take care of oneself, complete reliance on others for care, and / or significant sphincter disorders. The severity of cognitive impairment may be determined by clinical manifestations, daily ability impairment or cognitive assessment. For example, the severity of cognitive impairment may be diagnosed by the activity of daily living scale (ADL), the clinical dementia rating scale (CDR) or the global deterioration scale (GDS). In this application, the term "cognitive impairment due to normal aging" generally refers to cognitive impairment due to normal aging. For example, the cognitive impairment due to normal aging can be manifested as: memory loss, confusion about the location of familiar places, taking longer than usual to complete daily tasks, or changes in mood and personality. In this application, the term "lewy body dementia (LBD)" generally refers to Lewy Body Detmentia, Lewy body dementia. Lewy body dementia is characterized by abnormal accumulation of proteins into lumps called Lewy bodies. Lewy body dementia causes a gradual decline in mental abilities. People with Lewy body dementia may experience visual hallucinations and changes in alertness and attention. Other effects include muscle stiffness, slow movements, difficulty walking, and tremors. Patients with Lewy bodies in the brain can also have plaques and tangles associated with Alzheimer's disease. In this application, the term "frontotemporal dementia" generally refers to Pick's disease, a rare, progressive disease in which the tau protein affects only the frontal and temporal lobes of the brain. People with frontotemporal dementia have difficulty with higher-level reasoning, expressive language, language perception, and memory formation. The frontal and temporal lobes of the brain of people with frontotemporal dementia can shrink over time. In this application, the term "vascular dementia" generally refers to problems with reasoning, judgment, and memory due to impaired blood flow to the brain. For example, the vascular dementia may include dementia due to factors that increase risk of heart disease and stroke, such as high blood pressure and high cholesterol. In this application, the term "multiple infarcts" generally refers to small non-cortical infarcts caused by occlusion of a single perforator of a large cerebral artery. The multiple infarcts may be a special type of cerebral infarction, also known as ischemic stroke. The multiple infarcts may manifest as hemisensory disturbances, aphasia, dysarthria, slow movements, clumsiness (especially fine movements such as writing are more difficult). In this application, the term "Parkinson's disease" generally refers to a progressive neurodegenerative disease. The clinical features of Parkinson's disease (PD) may include motor symptoms (such as tremor, bradykinesia, rigidity, and postural instability), as well as neurological Psychiatric and other non-motor manifestations. For example, the non-motor manifestations may include cognitive dysfunction and dementia, mood disorders (e.g., depression, anxiety, apathy), and sleep disorders. In this application, the term "AIDS" generally refers to acquired immunodeficiency syndrome (AIDS). The clinical manifestations of AIDS include changes in memory, concentration, attention, and motor skills. In some cases, AIDS patients may develop cognitive impairment, for example, about 50% of infected people may further develop HIV-associated neurocognitive disorders (HAND). In this application, the term "CJD" generally refers to a transmissible spongiform encephalopathy that occurs in humans. CJD is a disease caused by prion infection. CJD patients may show paranoid behavior, confusion, loss of appetite and weight, depression, and a few patients have visual or auditory abnormalities; in the advanced stage, it manifests as progressive deterioration of the neurological condition (such as paresthesia, language disorders and aphasia). In this application, the term "multiple sclerosis (MS)" generally refers to a demyelinating neuropathy. The insulating material (i.e., myelin sheath) on the surface of nerve cells in the brain or spinal cord of the MS patient is damaged, and the signal transduction of the nervous system is impaired, which can lead to a series of possible symptoms that affect the patient's activities, mind, and even mental state. These symptoms can include double vision, unilateral visual impairment, muscle weakness, insensitivity, or coordination disorders. In this application, the term "amyotrophic lateral sclerosis (ALS)" generally refers to Lou Gehrig's disease, motor neuron disease, which is a progressive and fatal neurodegenerative disease. A small number of ALS patients may develop frontotemporal dementia. Some ALS patients will experience degeneration of their sense of smell, vision, touch, smell and taste, and a very small number of ALS patients will also develop dementia. In this application, the term "Huntington's disease (HD)" generally refers to a genetic disease that causes brain cell death. As the disease progresses, the uncoordinated movement of HD patients becomes more obvious, and their abilities gradually deteriorate until movement becomes difficult and speech is impossible. Mental abilities usually decline into dementia. In the present application, the term "senile stage" generally refers to the aging stage of a subject. For example, for humans, the senile stage may be over 60 years old, over 70 years old, or over 75 years old; for mice, the senile stage may be over 10 months old, for example, over 13 months old or over 18 months old. In some cases, the subject at the senile stage may have one or more symptoms of learning deficits, memory impairment, memory deficits, and / or brain dysfunction. In this application, the term "subject" generally refers to a human or non-human animal, including but not limited to a cat, dog, horse, pig, cow, sheep, rabbit, mouse, rat or monkey. In this application, the term "comprising" generally means including, encompassing, containing or encompassing. In some cases, it also means "for", "consisting of...". In this application, the term "about" generally refers to a numerical range of 20% more or less than a specific value. For example, "about X" includes The range of the present invention is inclusive of a numerical range of ±20%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2% or ±0.1% of X, where X is a numerical value. DETAILED DESCRIPTION OF THE INVENTION ATP6V1B2 and its functionally active fragments In the present application, the ATP6V1B2 may be derived from any organism. For example, the ATP6V1B2 may be derived from humans or mice. In the present application, the ATP6V1B2 may comprise the amino acid sequence shown in SEQ ID NO.8 or 16. In the present application, the functionally active fragment of ATP6V1B2 can be combined with the binding agent described in the present application. In the present application, the functionally active fragment of ATP6V1B2 can have the ability to specifically bind to the amino acid sequence shown in SEQ ID NO.5. For example, the functionally active fragment of ATP6V1B2 can include a truncate of ATP6V1B2. For example, the functionally active fragment of ATP6V1B2 can include at least a portion of the sequence of amino acids from positions 287 to 512 of the human ATP6V1B2 protein. For example, the functionally active fragment of ATP6V1B2 can include at least a portion of the sequence of amino acids from positions 287 to 512 of the mouse ATP6V1B2 protein. In the present application, the ATP6V1B2 and / or its functionally active fragment may comprise the amino acid sequence shown in any one of SEQ ID NOs: 8, 10-11, and 16. In the present application, the nucleic acid sequence encoding the ATP6V1B2 and / or its functionally active fragment may include the nucleic acid sequence shown in SEQ ID NO:9 or 17. In the present application, the activity of the ATP6V1B2 may include the biological activity of the ATP6V1B2 protein and / or its functionally active fragment (e.g., may include a measurable downstream effect caused by it). For example, the activity of the ATP6V1B2 may include increasing the expression level and / or activity of the proton pump-related protein. In the present application, the increase may include increasing the activity of the proton pump-related protein by at least about 10% compared to the activity of the original proton pump-related protein in the subject. For example, it may increase by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. ATP6V1B2 binders In one aspect, the present application provides a binding agent that is capable of binding to ATP6V1B2 and / or a functionally active fragment thereof. In the present application, the binding of the binding agent to ATP6V1B2 can be specific. For example, the binding agent can be greater than or equal to about 10 5 M -1 (For example, greater than or equal to about 10 5 M -1 , greater than or equal to about 10 6 M -1 , greater than or equal to about 10 7 M - 1 , greater than or equal to about 10 8 M -1 , greater than or equal to about 10 9 M -1 , greater than or equal to about 10 10 M -1 , greater than or equal to about 10 11 M- 1. Greater than or equal to about 10 12 M -1 , greater than or equal to about 10 13 M -1or greater) of Ka (i.e., the equilibrium association constant for the binding interaction, which is 1 / M); or, -5 M (e.g., less than or equal to about 10 -5 M, less than or equal to about 10 -6 M, less than or equal to about 10 -7 M, less than or equal to about 10 -8 M, less than or equal to about 10 -9 M, less than or equal to about 10 -10 M, less than or equal to about 10 -11 M, less than or equal to about 10 -12 M, less than or equal to about 10 -13 The binding agent may bind or associate with ATP6V1B2 with an equilibrium dissociation constant Kd of 4 M or less. For example, the binding of the binding agent to ATP6V1B2 and / or its functionally active fragment may be in vivo or in vitro. In the present application, the binding agent may include a small molecule compound, a polymer and / or a biomacromolecule. In the present application, the binding agent may include a protein and / or a polypeptide. In the present application, the binding agent may comprise the amino acid sequence shown in SEQ ID NO: 1 and / or SEQ ID NO: 2 and / or a variant thereof. For example, the binding agent may comprise a polypeptide having an amino terminal deletion, a carboxyl terminal deletion, and / or an internal deletion or substitution compared to the full length of the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2, while the remaining amino acid sequence is generally identical to the corresponding positions of the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2. For example, the binding agent may comprise a polypeptide having at least 60%, 70%, 80%, 90%, or 100% of the biological activity of the polypeptide of the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2. For example, the binding agent may comprise a protein or polypeptide in which one or more amino acids are substituted, deleted, or added in the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2. For example, the binding agent may comprise a polypeptide that has amino acid alterations by at least 1, e.g., 1, 2, 3, 4, 5 or more amino acid substitutions, deletions and / or insertions in the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2. For example, the binding agent can comprise a homolog of the amino acid sequence set forth in SEQ ID NO: 1 and / or SEQ ID NO: 2. For example, the binding agent can include a polypeptide having at least about 40% (e.g., having at least about 43%, about 50%, about 57%, about 60%, about 62.5%, about 70%, about 71%, about 75%, about 80%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 92%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO: 1 and / or SEQ ID NO: 2. In the present application, the binding agent may comprise the amino acid sequence shown in SEQ ID NO: 54 and / or SEQ ID NO: 55 and / or variants thereof. For example, the binding agent may comprise a polypeptide having an amino terminal deletion, a carboxyl terminal deletion, and / or an internal deletion or substitution compared to the full length of the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55, while the remaining amino acid sequence is generally identical to the corresponding positions of the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55. For example, the binding agent may comprise a polypeptide having at least 60%, 70%, 80%, 90%, or 100% of the biological activity of the polypeptide having the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55. For example, the binding agent may comprise a polypeptide having at least 60%, 70%, 80%, 90%, or 100% of the biological activity of the polypeptide having the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55. Proteins or polypeptides with one or more amino acids deleted or added. For example, the binding agent may comprise a polypeptide that has amino acid changes by at least one, such as one, two, three, four, five or more amino acid substitutions, deletions and / or insertions in the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55. For example, the binding agent can comprise a homolog of the amino acid sequence set forth in SEQ ID NO: 54 and / or SEQ ID NO: 55. For example, the binding agent can include a polypeptide having at least about 40% (e.g., having at least about 43%, about 50%, about 57%, about 60%, about 62.5%, about 70%, about 71%, about 75%, about 80%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 92%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO: 54 and / or SEQ ID NO: 55. In the present application, the binding agent may comprise the amino acid sequence shown in SEQ ID NO: 33 and / or a variant thereof, wherein X may be any amino acid. For example, the binding agent may comprise the amino acid sequence shown in any one of SEQ ID NO: 30-32 and / or a variant thereof, wherein X may be any amino acid. For example, the binding agent may comprise the amino acid sequence shown in any one of SEQ ID NO: 27-29 and / or a variant thereof, wherein X may be any amino acid. For example, the binding agent may comprise the amino acid sequence shown in any one of SEQ ID NO: 19-26 and / or a variant thereof, wherein X may be any amino acid. In the present application, the binding agent may include a polypeptide, and the polypeptide may have at least 7 amino acids. For example, the polypeptide may have at least 8 amino acids. In the present application, the binding agent may include a polypeptide with any number of amino acids containing the polypeptide sequence described in the present application. In the present application, the binding agent may include a polypeptide, and the amino acids from the N-terminus to the C-terminus of the polypeptide are represented by X1, X2, X3, X4, X5, X6, X7, X8, and so on. In a certain embodiment, X1 of the polypeptide may be serine, X2-X4 of the polypeptide may be any amino acids, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, and X7 of the polypeptide may be cysteine. For example, X2 of the polypeptide may be proline. For example, X2 of the polypeptide may be a conservative replacement amino acid for proline. For example, X2 of the polypeptide may be a non-conservative replacement amino acid for proline. For example, X2 of the polypeptide may be alanine. For example, X2 of the polypeptide may be a conservative replacement amino acid for alanine. For example, X2 of the polypeptide may be a non-conservative replacement amino acid for alanine. For example, X2 of the polypeptide may be a non-polar amino acid. For example, X2 of the polypeptide may be a polar amino acid. For example, X3 of the polypeptide may be valine. For example, X3 of the polypeptide may be a conservative replacement amino acid for valine. For example, X3 of the polypeptide may be a non-conservative replacement amino acid for valine. For example, X3 of the polypeptide may be alanine. For example, X3 of the polypeptide may be a conservative replacement amino acid for alanine. For example, X3 of the polypeptide may be For example, X3 of the polypeptide may be a non-polar amino acid. For example, X3 of the polypeptide may be a polar amino acid. For example, X4 of the polypeptide may be aspartic acid. For example, X4 of the polypeptide may be a conservative replacement amino acid of aspartic acid. For example, X4 of the polypeptide may be a non-conservative replacement amino acid of aspartic acid. For example, X4 of the polypeptide may be alanine. For example, X4 of the polypeptide may be a conservative replacement amino acid of alanine. For example, X4 of the polypeptide may be a non-conservative replacement amino acid of alanine. For example, X4 of the polypeptide may be a non-polar amino acid. For example, X4 of the polypeptide may be a polar amino acid. For example, the polypeptide may have X8, and X8 of the polypeptide may be any amino acid, for example, X8 of the polypeptide may be serine. For example, X8 of the polypeptide may be an amino acid conservatively substituted for serine. For example, X8 of the polypeptide may be a non-conservative substituted amino acid for serine. For example, X8 of the polypeptide may be a non-polar amino acid. For example, X8 of the polypeptide may be a polar amino acid. For example, the polypeptide may not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid, X3 of the polypeptide may be valine or alanine, X4 of the polypeptide may be aspartic acid or alanine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be proline or alanine, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be aspartic acid or alanine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be proline or alanine, X3 of the polypeptide may be valine or alanine, X4 of the polypeptide may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be aspartic acid or alanine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In one embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be proline or alanine, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, and X8 may be serine or the polypeptide may not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid, X3 of the polypeptide may be valine or alanine, X4 may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be any amino acid except glycine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be serine, X3 of the polypeptide may be any amino acid except cysteine, X4 of the polypeptide may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid except serine, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be serine, X3 of the polypeptide may be cysteine, X4 of the polypeptide may be any amino acid except glycine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be serine, X3 of the polypeptide may be any amino acid except cysteine, X4 of the polypeptide may be glycine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid except serine, X3 of the polypeptide may be cysteine, X4 of the polypeptide may be glycine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In the present application, the binding agent may include a polymer. For example, the polymer may include a dimer. For example, The multimer may include a homodimer. In the present application, the binding agent may be a polypeptide, the polypeptide may contain cysteine, and the cysteine ​​in the amino acid sequence of the polypeptide may not have a thiol-blocked modification. For example, if the cysteine ​​residue in the amino acid sequence of the polypeptide is blocked by a thiol group, it may lose the ability to bind to the ATP6V1B2 protein. In the present application, the binding agent may be a polypeptide, the polypeptide may contain serine, and the serine in the amino acid sequence of the polypeptide does not have phosphorylation modification. For example, if the serine residue in the amino acid sequence of the polypeptide is phosphorylated, it may lose the ability to bind to the ATP6V1B2 protein. In certain embodiments, the binding agent may be a polypeptide and the binding agent is capable of entering a cell. For example, the binding agent has the ability to penetrate the cell membrane and enter the cell even when it does not contain a membrane-penetrating peptide. In the present application, the binding agent may be a fusion protein and / or a fusion polypeptide. For example, the fusion protein and / or the fusion polypeptide may include a first part and a second part. For example, the fusion protein and / or the polypeptide may include a binding agent of ATP6V1B2 described in the present application and / or a polypeptide described in the present application as a first part. For example, the fusion protein and / or the polypeptide may include a part that is identical, different or not identical to the first part as a second part. For example, the first part and the second part are directly or indirectly connected. For example, the first part and the second part can be connected by a peptide bond. For example, the first part and the second part can be connected by a linker. For example, the first part and the second part can be connected by a non-peptide. For example, the second portion may have a specific function. For example, the second portion may be transported across the blood-brain barrier to the brain. For example, the second portion may comprise a molecule capable of being transported across the blood-brain barrier to the brain. For example, the molecule capable of being transported across the blood-brain barrier to the brain comprises a polypeptide. For example, the second portion may comprise a cell-penetrating peptide. For example, the cell-penetrating peptide is capable of being transported across the blood-brain barrier to the brain. For example, the second portion comprises an amino acid sequence as shown in SEQ ID NO: 34. For example, the second portion can bind to ATP6V1B2. For example, the second portion can completely, incompletely or not bind to ATP6V1B2 at all. For example, the second portion can affect the binding of the first portion to ATP6V1B2. For example, the second portion can enhance the binding ability of the first portion to ATP6V1B2. For example, compared with the binding ability of the first portion to ATP6V1B2, the fusion polypeptide or fusion protein comprising the first portion and the second portion has a stronger binding ability to ATP6V1B2. For example, compared with the binding ability of the first portion to ATP6V1B2, the fusion polypeptide or fusion protein comprising the first portion and the second portion has a stronger binding ability to ATP6V1B2 than the binding ability of the first portion to ATP6V1B2 than at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% or more. For example, the second part can weaken the binding ability of the first part to ATP6V1B2. For example, compared with the binding ability of the first part to ATP6V1B2, comprising The binding ability of the fusion polypeptide or fusion protein of the first part and the second part to ATP6V1B2 is weaker. For example, compared with the binding ability of the first part to ATP6V1B2, the binding ability of the fusion polypeptide or fusion protein comprising the first part and the second part to ATP6V1B2 is weaker than at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% or more. For example, the binding ability can be measured by technical means commonly used in the art. For example, the binding ability can be represented by the equilibrium dissociation constant Kd. For example, the binding ability can be determined by the method of immunocoprecipitation. For example, the fusion protein and / or polypeptide may include the binding agent of ATP6V1B2 described herein and / or the polypeptide described herein as a first part and a cell-penetrating peptide as a second part. For example, the binding agent of ATP6V1B2 and the cell-penetrating peptide may be linked by a peptide bond to form a fusion polypeptide and / or fusion protein. For example, the fusion protein and / or polypeptide may comprise an amino acid sequence and / or variant thereof as described in any one of SEQ ID NO: 48, wherein X is any amino acid. For example, the fusion protein and / or polypeptide may comprise an amino acid sequence and / or variant thereof as described in any one of SEQ ID NO: 45-47, wherein X is any amino acid. For example, the fusion protein and / or polypeptide may comprise an amino acid sequence and / or variant thereof as described in any one of SEQ ID NO: 42-44, wherein X is any amino acid. For example, the fusion protein and / or polypeptide may comprise an amino acid sequence and / or variant thereof as described in any one of SEQ ID NO: 35-41. In the present application, the binding agent can regulate the expression level and / or activity of proton pump-related proteins. For example, the binding agent can increase the expression level and / or activity of proton pump-related proteins. For example, the expression level of the proton pump-related protein includes the expression level of the gene encoding the proton pump-related protein, the transcription level of the gene encoding the proton pump-related protein, and / or the expression level of the proton pump-related protein. For example, the improvement includes that the expression level and / or activity of the proton pump-related protein is increased by at least about 10% compared with the expression level and / or activity of the original proton pump-related protein in the subject. In the present application, the improvement can include that the expression level of the proton pump-related protein is increased by at least about 5% compared with the expression level of the original proton pump-related protein in the subject. For example, it can be increased by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In certain embodiments, the ability of the binding agent described in the present application to increase the expression level and / or activity of a proton pump-related protein is stronger than the ability of QD202 to increase the expression level and / or activity of a proton pump-related protein. For example, the ability of SS8 described in the present application (whose amino acid sequence is shown in SEQ ID NO.54) to increase the expression level and / or activity of a proton pump-related protein is stronger than that of QD202 (whose amino acid sequence is shown in SEQ ID NO.1). For example, the expression level of proton pump-related proteins can be measured by conventional techniques in the art. But not limited to measuring the expression level of proton pump-related proteins by implementing an experiment selected from the following group: qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining and mass spectrometry. For example, the expression level of the proton pump-related protein can be measured by using, but not limited to, a substance selected from the following group: a primer capable of specifically amplifying a gene encoding a proton pump-related protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-related protein, a nucleic acid molecule that specifically binds to a proton pump-related protein, a small molecule that specifically binds to a proton pump-related protein, a probe that specifically binds to a proton pump-related protein, and a polypeptide that specifically binds to a proton pump-related protein. In the present application, the proton pump-related protein may include NADH dehydrogenase, coenzyme Q, succinate-coenzyme Q reductase, cytochrome c and / or coenzyme Q-cytochrome c reductase. In the present application, the activity of the proton pump associated protein may include the biological activity of the proton pump associated protein. For example, the activity of the proton pump-related protein can be measured by its ability to regulate lysosomal acidity. For example, the activity of the proton pump-related protein can be measured by the acidity level of the lysosome. Lysosomal acidity generally refers to the acidic environment inside the intracellular lysosome (lysosome), which is usually maintained by the vesicle-type proton pump (V-ATPase) on the lysosomal membrane. The main function of the lysosomal V-ATPase is to transport protons on the negative side of the cell to the lysosomal chamber, thereby maintaining or increasing the acidic environment of the lysosome. ATP6V1B2 participates in the formation of the proton pump, can regulate the activity of the proton pump, and can directly affect the proton (H+ ion) concentration in the lysosome. For example, the activity of the proton pump-related protein can be regulated by the hydrogen / potassium ATPase system (also known as hydrogen / potassium ion ATPase, i.e., H + / K + ATPase) activity level; and / or H2 receptor activity level to measure. In the present application, the increase in the activity of the proton pump-related protein may include an increase in the activity of the proton pump-related protein by at least about 5% compared to the activity of the original proton pump-related protein in the subject. For example, it can be increased by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the binding agent can regulate the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the binding agent can increase the expression level and / or biological activity of ATP6V1B2. In the present application, the increase can include an increase of at least about 10% in the expression level of the ATP6V1B2 compared to the expression level of the original ATP6V1B2 in the subject. For example, it can increase by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In certain embodiments, in certain embodiments In the formula, the ability of the binding agent described in the present application to increase the expression level and / or biological activity of ATP6V1B2 is stronger than that of QD202. For example, the ability of SS8 described in the present application (whose amino acid sequence is shown in SEQ ID NO.54) to increase the expression level and / or biological activity of ATP6V1B2 is stronger than that of QD202 (whose amino acid sequence is shown in SEQ ID NO.1). For example, the expression level of ATP6V1B2 includes the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein. For example, the expression level may include the amount of a specific gene (e.g., human ATP6V1B2 gene) polynucleotide, mRNA or amino acid product or protein. The expression level may include the amount of a fragment of a polynucleotide transcribed from a specific gene (e.g., human ATP6V1B2 gene), a translated protein or a post-translationally modified protein. For example, the expression level of ATP6V1B2 can be measured by conventional techniques in the art. For example, including but not limited to measuring the expression level of ATP6V1B2 by implementing an experiment selected from the group consisting of: qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, protein blotting, immunohistochemistry, immunostaining, and mass spectrometry. For example, the expression level of ATP6V1B2 can be measured, but not limited to, by using a substance selected from the group consisting of: a primer capable of specifically amplifying the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 protein, a small molecule that specifically binds to the ATP6V1B2 protein, a probe that specifically binds to the ATP6V1B2 protein, and a polypeptide that specifically binds to the ATP6V1B2 protein. In the present application, the binding agent can improve cognitive ability. For example, the cognitive ability can include cognitive ability that can be measured by a novel object recognition behavior experiment. For example, the cognitive ability can include cognitive ability that can be measured by a water maze behavior experiment. For example, the improvement can include that the cognitive ability of the subject is improved after the binding agent is administered to the subject. For example, the improvement of the cognitive ability of the subject can include that in a water maze behavior experiment, the time spent by the subject in the quadrant where the platform is located is increased, the interval time of entering the quadrant where the platform is located is reduced, and / or the number of times the quadrant where the platform is located is increased. In certain embodiments, the degree of improvement of cognitive ability by the binding agent described in the present application is greater than the degree of improvement of cognitive ability by QD202. For example, the degree of improvement of cognitive ability by SS8 described in the present application (whose amino acid sequence is shown in SEQ ID NO.54) is greater than the degree of improvement of cognitive ability by QD202 (whose amino acid sequence is shown in SEQ ID NO.1). In the present application, the binding agent can increase the release of neuronal synaptic transmitters. For example, the increase includes an increase of at least about 10% compared to the level of original neuronal synaptic transmitter release in the subject. For example, the ability of the binding agent described in the present application to increase the release of neuronal synaptic transmitters can be increased by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In certain embodiments, the ability of the binding agent described in the present application to increase the release of neuronal synaptic transmitters is stronger than the ability of QD202 to increase the release of neuronal synaptic transmitters. For example, the SS8 described in the present application (whose amino acid sequence is shown in SEQ ID NO.54) increases The ability of QD202 (whose amino acid sequence is shown in SEQ ID NO.1) to increase the release of neuronal synaptic transmitter is greater than that of QD202 (whose amino acid sequence is shown in SEQ ID NO.1). In the present application, the binding agent is capable of increasing the firing frequency of excitatory postsynaptic currents. In the present application, the increase includes an increase of at least about 10% compared to the level of the firing frequency of the original excitatory postsynaptic current in the subject. For example, it can increase by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In certain embodiments, the ability of the binding agent described in the present application to increase the firing frequency of excitatory postsynaptic currents is stronger than the ability of QD202 to increase the firing frequency of excitatory postsynaptic currents. For example, the SS8 described in the present application (whose amino acid sequence is shown in SEQ ID NO.54) increases the firing frequency of excitatory postsynaptic currents greater than the firing frequency of excitatory postsynaptic currents increased by QD202 (whose amino acid sequence is shown in SEQ ID NO.1). In the present application, the binding agent can regulate lysosomal acidity and / or affect the ability to regulate lysosomal acidity. For example, the binding agent can increase lysosomal acidity. For example, the increase in lysosomal acidity can include an increase in the concentration of H+ ions in the lysosome. In the present application, the increase can include an increase of at least about 10% compared to the original proton concentration in the lysosome in the subject. For example, it can increase by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. For example, lysosomal acidity can be detected by a pH-sensitive fluorescent probe. In certain embodiments, the ability of the binding agent described in the present application to regulate lysosomal acidity and / or affect the ability to regulate lysosomal acidity is stronger than the ability of QD202 to regulate lysosomal acidity and / or affect the ability to regulate lysosomal acidity. For example, the ability of SS8 (whose amino acid sequence is shown in SEQ ID NO.54) described in the present application to regulate lysosomal acidity and / or influence the regulation of lysosomal acidity is stronger than the ability of QD202 (whose amino acid sequence is shown in SEQ ID NO.1) to regulate lysosomal acidity and / or influence the regulation of lysosomal acidity. Isolated peptides In another aspect, the present application provides isolated polypeptides. In the present application, the polypeptide may comprise the amino acid sequence shown in SEQ ID NO: 1 and / or SEQ ID NO: 2 and / or variants thereof. For example, the polypeptide may comprise a polypeptide having an amino terminal deletion, a carboxyl terminal deletion, and / or an internal deletion or substitution compared to the full length of the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2, while the remaining amino acid sequence is generally identical to the corresponding positions of the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2. For example, the polypeptide may comprise a polypeptide having at least 60%, 70%, 80%, 90%, or 100% of the biological activity of the polypeptide having the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2. For example, the polypeptide may comprise a polypeptide having substituted, deleted, or added one or more amino acids in the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2. For example, the polypeptide may include a polypeptide having amino acid changes by at least one, such as one, two, three, four, five or more amino acid substitutions, deletions and / or insertions in the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2. For example, the polypeptide may include a homolog of the amino acid sequence shown in SEQ ID NO: 1 and / or SEQ ID NO: 2. For example, the polypeptide may include a polypeptide having at least about 40% (e.g., at least about 43%, about 50%, about 57%, about 60%, about 62.5%, about 70%, about 71%, about 75%, about 80%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 92%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence shown in SEQ ID NO: 1 and / or SEQ ID NO: 2. In the present application, the polypeptide may include the amino acid sequence shown in SEQ ID NO: 54 and / or SEQ ID NO: 55 and / or variants thereof. For example, the polypeptide may include a polypeptide having an amino terminal deletion, a carboxyl terminal deletion, and / or an internal deletion or substitution compared to the full length of the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55, while the remaining amino acid sequence is generally the same as the corresponding positions of the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55. For example, the polypeptide may include a polypeptide having at least 60%, 70%, 80%, 90%, or 100% of the biological activity of the polypeptide of the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55. For example, the polypeptide may include a protein or polypeptide in which one or more amino acids are substituted, deleted or added in the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55. For example, the polypeptide may include a polypeptide that has amino acid changes by at least 1, such as 1, 2, 3, 4, 5 or more amino acid substitutions, deletions and / or insertions in the amino acid sequence shown in SEQ ID NO: 54 or SEQ ID NO: 55. For example, the polypeptide may comprise a homolog of the amino acid sequence shown in SEQ ID NO: 54 and / or SEQ ID NO: 55. For example, the polypeptide may include a polypeptide having at least about 40% (e.g., at least about 43%, about 50%, about 57%, about 60%, about 62.5%, about 70%, about 71%, about 75%, about 80%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 92%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence shown in SEQ ID NO: 54 and / or SEQ ID NO: 55. In the present application, the polypeptide may comprise the amino acid sequence shown in SEQ ID NO: 33 and / or a variant thereof, wherein X may be any amino acid. For example, the polypeptide may comprise the amino acid sequence shown in any one of SEQ ID NO: 30-32 and / or a variant thereof, wherein X may be any amino acid. For example, the polypeptide may comprise the amino acid sequence shown in any one of SEQ ID NO: 27-29 and / or a variant thereof, wherein X may be any amino acid. For example, the polypeptide may comprise the amino acid sequence shown in any one of SEQ ID NO: 19-26 and / or a variant thereof, wherein X may be any amino acid. In the present application, the polypeptide may include a polypeptide, and the polypeptide may have at least 7 amino acids. For example, the polypeptide may have at least 8 amino acids. In the present application, the polypeptide may include a polypeptide comprising the polypeptide sequence described in the present application. A polypeptide having any number of amino acids. In the present application, the polypeptide may include a polypeptide, wherein the amino acids from the N-terminus to the C-terminus of the polypeptide are represented by X1, X2, X3, X4, X5, X6, X7, X8, and so on. In a certain embodiment, X1 of the polypeptide may be serine, X2-X4 of the polypeptide may be any amino acids, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, and X7 of the polypeptide may be cysteine. For example, X2 of the polypeptide may be proline. For example, X2 of the polypeptide may be a conservative replacement amino acid for proline. For example, X2 of the polypeptide may be a non-conservative replacement amino acid for proline. For example, X2 of the polypeptide may be alanine. For example, X2 of the polypeptide may be a conservative replacement amino acid for alanine. For example, X2 of the polypeptide may be a non-conservative replacement amino acid for alanine. For example, X2 of the polypeptide may be a non-polar amino acid. For example, X2 of the polypeptide may be a polar amino acid. For example, X3 of the polypeptide may be valine. For example, X3 of the polypeptide may be a conservative replacement amino acid of valine. For example, X3 of the polypeptide may be a non-conservative replacement amino acid of valine. For example, X3 of the polypeptide may be alanine. For example, X3 of the polypeptide may be a conservative replacement amino acid of alanine. For example, X3 of the polypeptide may be a non-conservative replacement amino acid of alanine. For example, X3 of the polypeptide may be a non-polar amino acid. For example, X3 of the polypeptide may be a polar amino acid. For example, X4 of the polypeptide may be aspartic acid. For example, X4 of the polypeptide may be a conservative replacement amino acid of aspartic acid. For example, X4 of the polypeptide may be a non-conservative replacement amino acid of aspartic acid. For example, X4 of the polypeptide may be alanine. For example, X4 of the polypeptide may be a conservative replacement amino acid of alanine. For example, X4 of the polypeptide may be a non-conservative replacement amino acid of alanine. For example, X4 of the polypeptide may be a non-polar amino acid. For example, X4 of the polypeptide may be a polar amino acid. For example, the polypeptide may have X8, and X8 of the polypeptide may be any amino acid, for example, X8 of the polypeptide may be serine. For example, X8 of the polypeptide may be an amino acid conservatively substituted for serine. For example, X8 of the polypeptide may be a non-conservative substituted amino acid for serine. For example, X8 of the polypeptide may be a non-polar amino acid. For example, X8 of the polypeptide may be a polar amino acid. For example, the polypeptide may not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid, X3 of the polypeptide may be valine or alanine, X4 of the polypeptide may be aspartic acid or alanine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In one embodiment, X1 of the polypeptide may be serine, and X2 of the polypeptide may be proline or alanine. Acid, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be aspartic acid or alanine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be proline or alanine, X3 of the polypeptide may be valine or alanine, X4 of the polypeptide may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be aspartic acid or alanine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be proline or alanine, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid, X3 of the polypeptide may be valine or alanine, X4 may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be any amino acid except glycine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be serine, X3 of the polypeptide may be any amino acid except cysteine, X4 of the polypeptide may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In one embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid except serine, X3 of the polypeptide may be any amino acid, X4 of the polypeptide may be any amino acid, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, and X7 of the polypeptide may be cysteine. X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be serine, X3 of the polypeptide may be cysteine, X4 of the polypeptide may be any amino acid except glycine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be serine, X3 of the polypeptide may be any amino acid except cysteine, X4 of the polypeptide may be glycine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In a certain embodiment, X1 of the polypeptide may be serine, X2 of the polypeptide may be any amino acid except serine, X3 of the polypeptide may be cysteine, X4 of the polypeptide may be glycine, X5 of the polypeptide may be valine, X6 of the polypeptide may be valine, X7 of the polypeptide may be cysteine, X8 of the polypeptide may be serine or the polypeptide does not have X8. In the present application, the polypeptide may include a polymer. For example, the polymer may include a dimer. For example, the polymer may include a homodimer. In the present application, the cysteine ​​residues in the amino acid sequence of the polypeptide may not have sulfhydryl blocking modifications. For example, if the cysteine ​​residues in the amino acid sequence of the polypeptide are blocked by sulfhydryl groups, they may lose the ability to bind to the ATP6V1B2 protein. In the present application, the serine in the amino acid sequence of the polypeptide does not have phosphorylation modification. For example, if the serine residue in the amino acid sequence of the polypeptide is phosphorylated, it may lose the ability to bind to the ATP6V1B2 protein. In the present application, the isolated polypeptide can be used as a binder of ATP6V1B2. In the present application, the isolated polypeptide can be used to prepare a binder of ATP6V1B2. In the present application, the isolated polypeptide can have one or more functions of an ATP6V1B2 binder. For example, the polypeptide can regulate the expression level and / or activity of a proton pump-related protein. For example, the polypeptide can regulate the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the polypeptide can increase the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the polypeptide can improve cognitive ability. For example, the polypeptide can increase neuronal synaptic transmitter release. For example, the polypeptide can increase the frequency of excitatory postsynaptic current discharge. For example, the polypeptide can treat cognitive disorders and / or neurodegenerative diseases. For example, the polypeptide can regulate lysosomal acidity and / or affect the ability to regulate lysosomal acidity. For example, the polypeptide can prevent and / or treat diseases associated with lysosomes. For example, the disease associated with lysosome can include a disease associated with lysosome abnormality. For example, the disease associated with lysosome can include a disease associated with lysosome acidity abnormality. sick. Fusion protein / fusion peptide In another aspect, the present application provides fusion proteins and / or fusion polypeptides. In the present application, the fusion protein and / or fusion polypeptide may comprise the binding agent and / or the polypeptide described in the present application. For example, the fusion protein and / or fusion polypeptide may include a first part and a second part. For example, the fusion protein and / or polypeptide may include a binding agent of ATP6V1B2 described herein and / or a polypeptide described herein as a first part. For example, the fusion protein and / or polypeptide may include a part that is identical, different, or not identical to the first part as a second part. For example, the first part and the second part are directly or indirectly connected. For example, the first part and the second part can be connected by a peptide bond. For example, the first part and the second part can be connected by a linker. For example, the first part and the second part can be connected by a non-peptide. For example, the second portion may have a specific function. For example, the second portion may be transported across the blood-brain barrier to the brain. For example, the second portion may comprise a molecule capable of being transported across the blood-brain barrier to the brain. For example, the molecule capable of being transported across the blood-brain barrier to the brain comprises a polypeptide. For example, the second portion may comprise a cell-penetrating peptide. For example, the cell-penetrating peptide is capable of being transported across the blood-brain barrier to the brain. For example, the second portion comprises an amino acid sequence as shown in SEQ ID NO: 34. For example, the second portion can bind to ATP6V1B2. For example, the second portion can completely, incompletely or not bind to ATP6V1B2 at all. For example, the second portion can affect the binding of the first portion to ATP6V1B2. For example, the second portion can enhance the binding ability of the first portion to ATP6V1B2. For example, compared with the binding ability of the first portion to ATP6V1B2, the fusion polypeptide or fusion protein comprising the first portion and the second portion has a stronger binding ability to ATP6V1B2. For example, compared with the binding ability of the first portion to ATP6V1B2, the fusion polypeptide or fusion protein comprising the first portion and the second portion has a stronger binding ability to ATP6V1B2 than the binding ability of the first portion to ATP6V1B2 than at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% or more. For example, the second part can weaken the binding ability of the first part to ATP6V1B2. For example, the binding ability of the fusion polypeptide or fusion protein comprising the first part and the second part to ATP6V1B2 is weaker than the binding ability of the first part to ATP6V1B2. For example, the binding ability of the fusion polypeptide or fusion protein comprising the first part and the second part to ATP6V1B2 is weaker than at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% compared to the binding ability of the first part to ATP6V1B2. or more. For example, the binding capacity can be measured by conventional techniques in the art. For example, the binding capacity can be represented by the equilibrium dissociation constant Kd. For example, the binding capacity can be measured by immunocoprecipitation. For example, the fusion protein and / or polypeptide may include the binding agent of ATP6V1B2 described herein and / or the polypeptide described herein as a first part and a cell-penetrating peptide as a second part. For example, the binding agent of ATP6V1B2 and the cell-penetrating peptide may be linked by a peptide bond to form a fusion polypeptide and / or fusion protein. For example, the fusion protein and / or polypeptide may comprise an amino acid sequence and / or variant thereof as described in any one of SEQ ID NO: 48, wherein X is any amino acid. For example, the fusion protein and / or polypeptide may comprise an amino acid sequence and / or variant thereof as described in any one of SEQ ID NO: 45-47, wherein X is any amino acid. For example, the fusion protein and / or polypeptide may comprise an amino acid sequence and / or variant thereof as described in any one of SEQ ID NO: 42-44, wherein X is any amino acid. For example, the fusion protein and / or polypeptide may comprise an amino acid sequence and / or variant thereof as described in any one of SEQ ID NO: 35-41. In the present application, the fusion protein and / or fusion polypeptide can be used as a binder of ATP6V1B2. In the present application, the fusion protein and / or fusion polypeptide can be used to prepare a binder of ATP6V1B2. In the present application, the fusion protein and / or fusion polypeptide can have one or more functions of an ATP6V1B2 binder. For example, the fusion protein and / or fusion polypeptide can regulate the expression level and / or activity of a proton pump-related protein. For example, the fusion protein and / or fusion polypeptide can regulate the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the fusion protein and / or fusion polypeptide can increase the expression level and / or biological activity of ATP6V1B2 and / or its functionally active fragments. For example, the fusion protein and / or fusion polypeptide can improve cognitive ability. For example, the fusion protein and / or fusion polypeptide can increase neuronal synaptic transmitter release. For example, the fusion protein and / or fusion polypeptide can increase the frequency of discharge of excitatory postsynaptic currents. For example, the fusion protein and / or fusion polypeptide can prevent and / or treat cognitive impairment and / or neurodegenerative diseases. For example, the fusion protein and / or fusion polypeptide can regulate lysosomal acidity and / or affect the regulation and control ability of lysosomal acidity. For example, the fusion protein and / or fusion polypeptide can prevent and / or treat diseases associated with lysosomes. For example, the diseases associated with lysosomes can include diseases associated with lysosomal abnormalities. For example, the diseases associated with lysosomes can include diseases associated with abnormal lysosomal acidity. Immunoconjugates In another aspect, the present application provides an immunoconjugate, which comprises the binding agent described in the present application, the polypeptide described in the present application and / or the fusion polypeptide described in the present application. For example, the immunoconjugate may include 1, 2 or more binding agents described herein, polypeptides described herein and / or polypeptides described herein. The immunoconjugates described herein have biological activity. For example, the biological activity may include binding in vivo or in vitro The immunoconjugate can regulate lysosomal acidity and / or affect the regulation ability of lysosomal acidity. For example, the immunoconjugate can prevent and / or treat diseases related to lysosomes. Nucleic acid molecules, vectors, cells The present application provides one or more nucleic acid molecules, which can encode the binding agent described in the present application, the polypeptide described in the present application, the fusion polypeptide described in the present application, and / or the immunoconjugate described in the present application. For example, each of the one or more nucleic acid molecules can encode the complete binding agent, the polypeptide, the fusion polypeptide, or the immunoconjugate, or a portion thereof. The nucleic acid molecules described herein can be isolated. For example, they can be produced or synthesized by the following methods: (i) amplified in vitro, such as produced by polymerase chain reaction (PCR) amplification, (ii) produced by cloning and recombination, (iii) purified, such as by enzyme cutting and gel electrophoresis fractionation, or (iv) synthesized, such as by chemical synthesis. In some embodiments, the isolated nucleic acid is a nucleic acid molecule prepared by recombinant DNA technology. Recombinant DNA and molecular cloning techniques include those described by Sambrook, J., Fritsch, EF and Maniatis, T. Molecular Cloning: A Laboratory Manual; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, (1989) (Maniatis) and by TJ Silhavy, ML Bennan and LV Enquist, Experiments with Gene Fusions, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1984) and by Ausubel, FM et al., Current Protocols in Molecular Biology, pub. by Greene Publishing Assoc. and Wiley-Interscience (1987). Briefly, the nucleic acids can be prepared from genomic DNA fragments, cDNA and RNA, all of which can be extracted directly from cells or recombinantly produced by various amplification methods (including but not limited to PCR and RT-PCR). In another aspect, the application provides one or more vectors comprising the nucleic acid molecules. For example, the vector may contain one or more nucleic acid molecules. In addition, the vector may also contain other genes, such as marker genes that allow the vector to be selected in a suitable host cell and under suitable conditions. In addition, the vector may also contain expression control elements that allow the coding region to be correctly expressed in a suitable host. Such control elements are well known to those skilled in the art, for example, may include promoters, ribosome binding sites, enhancers and other control elements that regulate gene transcription or mRNA translation, etc. The one or more nucleic acid molecules described in the application may be operably connected to the expression control elements. The vector may include, for example, a plasmid, a cosmid, a virus, a phage or other vectors commonly used in, for example, genetic engineering. For example, the vector is an expression vector. In another aspect, the present application provides a cell, which may contain one or more binding agents described in the present application, one or more polypeptides described in the present application, one or more fusion polypeptides described in the present application, one or more In some embodiments, each or each host cell may contain one or more nucleic acid molecules or vectors described in the present application. In some embodiments, each or each host cell may contain multiple (e.g., 2 or more) or multiple (e.g., 2 or more) nucleic acid molecules or vectors described in the present application. The vectors described in the present application may be introduced into the cells by methods known in the art, such as electroporation, liposome transfection, etc. Drug combination / drug composition On the other hand, the present application provides a pharmaceutical composition, which may include the binding agent described in the present application, the polypeptide described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application and / or the cell described in the present application. On the other hand, the present application provides a pharmaceutical composition, which may include the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein, and optionally a pharmaceutically acceptable carrier. For example, the pharmaceutical composition may include a pharmaceutical product suitable for pharmaceutical uses (e.g., improving learning ability, treating cognitive impairment and / or treating neurodegenerative diseases (e.g., Alzheimer's disease)). For example, the pharmaceutical composition may be used to prevent and / or treat neurodegenerative diseases. For example, the pharmaceutical composition may be used to prevent and / or treat a disease associated with a lysosome. For example, the disease associated with a lysosome may include a disease associated with a lysosomal abnormality. For example, the disease associated with a lysosome may include a disease associated with abnormal lysosomal acidity. For example, the pharmaceutical composition can be a composition comprising one or more active ingredients (such as the binding agents described herein) and one or more inert ingredients; as well as any product obtained directly or indirectly from the combination, complex or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. For example, the pharmaceutically acceptable carrier may include sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles may include water, ethanol, polyols (e.g., propylene glycol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters such as ethyl oleate. Reagent test kit On the other hand, the present application provides a kit comprising the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein and / or the cell described herein; and one or more additional components selected from the following group: analytical buffer, controls, substrates, standards, detection materials, laboratory supplies, equipment, instruments, cells, organs, tissues and user manuals or instructions. In the present application, the kit can detect ATP6V1B2 in a sample. For example, the kit can detect the expression level and / or biological activity of ATP6V1B2 and / or its functional fragments. For example, the detection kit can include instructions, which record the specific steps of how to use the kit to detect the expression level and / or biological activity of ATP6V1B2 and / or its functional fragments, and / or how to use the test results to determine whether the candidate drug can prevent and / or treat cognitive impairment and / or treat subjects with neurodegenerative diseases. Learning ability In the present application, when the expression level and / or activity of ATP6V1B2 in the subject is increased, the learning ability of the subject can be significantly improved (for example, the cognitive ability, motor ability, memory ability and / or spatial exploration ability can be significantly improved compared to before the expression level and / or activity of ATP6V1B2 in the subject is increased). Therefore, ATP6V1B2 can be used as a potential target for improving learning ability. For example, ATP6V1B2 can be used as a potential target for treating neurodegenerative diseases (such as Alzheimer's disease) and / or cognitive disorders. In the present application, the learning ability may include all abilities related to or required for the learning / cognitive process. For example, the learning ability may include cognitive ability, motor ability, memory ability and / or spatial exploration ability. In the present application, the improvement of the learning ability can include that the assessment score of the learning ability of the experimenter after the improvement is improved by at least about 50% compared with the assessment score of the original learning ability of the experimenter. For example, it can be improved by at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the assessment score of the learning ability can be obtained by conducting a score including attention / executive function assessment (e.g., Wechsler Memory Test), language ability assessment (e.g., language screening test (LAST)), visual-spatial and structural ability assessment (e.g., visual-motor integration test, Hooper visual organization test, object assembly test, graphic arrangement test, clock drawing test), application ability assessment, daily function assessment (e.g., disability assessment for dementia (DAD)) and / or neuropsychological scale. For example, the assessment score of the learning ability can be measured by implementing a test selected from the following group: a novel object recognition test and a water maze test. In the present application, the novel object recognition test can evaluate the cognitive ability, motor ability and / or spatial exploration ability. In the present application, the novel object recognition test can make a subject (e.g., mouse) explore and learn an object of a specific shape in a fixed container, and distinguish a new object that is different from the previous object shape in the fixed container after a few days according to the memory obtained by learning. If the time for mice to distinguish the new object with different shapes after a few days is shorter, the learning ability of mice is correspondingly higher. The water maze evaluation test can be an important experiment for evaluating the learning ability of a subject. In the present application, the water maze test can evaluate the memory ability, motor ability and / or spatial exploration ability. In the present application, the water maze test (such as Morris water maze) can force the subject (such as mouse) to swim, thereby Learning to find a platform hidden in the water can test the mouse's spatial exploration ability and / or memory ability for spatial position and direction. The water maze test can also include acquisition training, exploration training, position training, or position exploration training. If the time required for the mouse to find the platform from entering the water is shorter and the distance moved during this period is shorter, the mouse's learning ability is correspondingly higher. The water maze evaluation test can be an important experiment to evaluate the learning ability of the subject. The present application provides the use of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in the preparation of an agent that can improve learning ability. The present application provides uses of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in improving learning ability. The present application provides a method for improving learning ability, which comprises administering to a subject in need thereof the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein. Prevent and / or treat disease The present application provides the use of the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein and / or the pharmaceutical composition described herein in the preparation of an agent for preventing and / or treating a disease. The present application provides a method for preventing and / or treating a disease, which comprises administering to a subject in need thereof the binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the drug combination described herein, the pharmaceutical composition described herein and / or the reagent for preventing and / or treating a disease described herein. The present application provides the use of the binding agent described in the present application, the polypeptide described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the drug combination described in the present application and / or the pharmaceutical composition described in the present application in preventing and / or treating diseases. For example, wherein the disease may include cognitive disorders. For example, wherein the disease may include neurodegenerative diseases. The agents described herein can be administered in any manner. For example, the agents described herein can be administered orally and / or by injection. For example, the agents described herein can be formulated into a form suitable for their mode of use. For example, the agents described herein can be administered orally and / or by injection. The agent may be formulated for oral administration and / or injection. For example, wherein the disease can include a disease associated with a lysosome. For example, the disease associated with a lysosome can include a disease associated with a lysosomal abnormality. For example, the disease associated with a lysosome can include a disease associated with a lysosomal acidity abnormality. The binding agent described herein, the polypeptide described herein, the fusion polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the pharmaceutical composition described herein, and / or the reagent for preventing and / or treating a disease described herein can be administered in a therapeutically effective dose. For example, a therapeutically effective dose may include an amount that effectively prevents or improves the symptoms of one or more diseases or conditions or the development of the disease or condition when administered to a subject. For example, a therapeutically effective dose may include an amount of a binding compound sufficient to cause symptom improvement, such as an amount that treats, cures, prevents or improves a related medical condition or increases the speed of treatment, cure, prevention or improvement of such conditions. For example, when a single active ingredient is administered to an individual, the therapeutically effective dose refers only to the ingredient. For example, when administered in combination, a therapeutically effective dose refers to the combined amount of active ingredients that cause a therapeutic effect, whether in combination, administered sequentially or administered simultaneously. In the present application, the prevention and / or treatment not only includes the prevention and / or treatment of the disease, but also generally includes preventing the onset of the disease, slowing down or reversing the progression of the disease, preventing or slowing down the onset of one or more symptoms associated with the disease, reducing and / or alleviating one or more symptoms associated with the disease, reducing the severity and / or duration of the disease and / or any symptom associated therewith and / or preventing the disease and / or any symptom associated therewith from further increasing in severity, preventing, reducing or reversing any physiological damage caused by the disease, and any pharmacological effect that is generally beneficial to the patient being treated. For example, the binding agent described in the present application, the polypeptide described in the present application, the fusion polypeptide described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the pharmaceutical composition described in the present application and / or the reagent for preventing and / or treating the disease described in the present application do not need to achieve complete cure or eradication of any symptom or manifestation of the disease. As recognized in the relevant art, a drug used as a therapeutic agent can reduce the severity of a given disease state, but does not need to eliminate every manifestation of the disease to be considered a useful therapeutic agent. Similarly, a prophylactically administered treatment does not need to be completely effective in preventing the onset of a condition to constitute a viable prophylactic. It is sufficient to simply reduce the effects of the disease in the subject (e.g., by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or to reduce the likelihood of the disease occurring or worsening. Detection of ATP6V1B2 The present application provides a method for detecting ATP6V1B2 in a sample, the method comprising administering the binding agent described in the present application, the polypeptide described in the present application, the fusion protein described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the pharmaceutical composition described in the present application and / or the Reagent test kit. The present application provides the use of the binding agent described in the present application, the polypeptide described in the present application, the fusion protein described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the pharmaceutical composition described in the present application and / or the kit described in the present application in the preparation of a kit. For example, the kit can be used to detect ATP6V1B2 in a sample. In the present application, ATP6V1B2 in a sample can be detected by detecting the binding of the binding agent described in the present application, the polypeptide described in the present application, the fusion protein described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the pharmaceutical composition described in the present application, and / or the kit described in the present application in the preparation of the kit and ATP6V1B2. For example, the detection may include direct detection. For example, the detection may include indirect detection. For example, the detecting of ATP6V1B2 in a sample as described herein may include detecting whether ATP6V1B2 exists in the sample. For example, the detecting of ATP6V1B2 in a sample as described herein may include detecting the content of ATP6V1B2 in the sample. For example, the ATP6V1B2 may include ATP6V1B2 and / or a nucleic acid encoding ATP6V1B2. The detection of ATP6V1B2 in a sample described in the present application may include contacting the binding agent described in the present application, the polypeptide described in the present application, the fusion protein described in the present application, the immunoconjugate described in the present application, the nucleic acid molecule described in the present application, the vector described in the present application, the cell described in the present application, the pharmaceutical composition described in the present application and / or the kit described in the present application with the sample. For example, the detection process may include forming a binding agent-ATP6V1B2 complex. For example, the binding agent-ATP6V1B2 complex can release ATP6V1B2 and then be used for detection and analysis, or the binding agent-ATP6V1B2 complex can be directly used for detection. For example, the method provided herein may directly detect the sample. For example, the method provided herein may only include contacting the sample with a binding agent. For example, the method provided herein may only include contacting the sample with a binding agent and detecting its binding. For example, the method provided herein may include contacting the sample with a binding agent, removing non-specifically bound substances, and detecting its binding. For example, the binding agent described herein, the polypeptide described herein, the fusion protein described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the pharmaceutical composition described herein and / or the kit described herein can be connected to a carrier. For example, the binding agent is directly or indirectly connected to a carrier such as a magnetic bead or a resin or a mixture thereof. For example, the binding agent can also be directly or indirectly connected to a solid surface or substrate. For example, the binding agent can also be bound to particles, such as beads or microspheres. For example, the binding agent can also be labeled with the following substances, including but not limited to magnetic markers, fluorescent moieties, enzymes, chemiluminescent probes, metal particles, non-metallic colloidal particles, polymer dye particles, pigment molecules, pigment particles, electrochemically active substances, semiconductor nanocrystals or other nanoparticles (including quantum dots or gold particles). Subjects and Indications In the present application, the subject may include a mammal. For example, the subject may include a rodent and / or a primate, for example, the subject may include a human. In the present application, the subject may include non-cognitive disorder patients and / or non-neurodegenerative disease patients. For example, the subject may be a normal person and / or a healthy person. For example, the subject may have a need and / or desire to further improve its learning ability. In the present application, the neurodegenerative disease may include acute neurodegenerative disease and chronic neurodegenerative disease. For example, the neurodegenerative disease may include neurodegenerative disease caused by neuronal death and glial cell homeostasis, neurodegenerative disease caused by aging, neurodegenerative disease caused by CNS cell function being affected, neurodegenerative disease caused by abnormal intercellular communication and / or neurodegenerative disease caused by impaired cell movement. In the present application, the subject may include a patient with a neurodegenerative disease. For example, the subject may include a patient with Alzheimer's disease. For example, the patient with Alzheimer's disease may be in the early, early, middle or late stages of Alzheimer's disease. In the present application, the cognitive impairment may include mild cognitive impairment (MCI), moderate cognitive impairment and severe cognitive impairment. For example, the cognitive impairment may include cognitive impairment caused by normal aging, Lewis body dementia (LBD), frontotemporal dementia and / or vascular dementia. For example, the induced disease of the cognitive impairment may include Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). In the present application, the subject may include a patient with cognitive impairment. For example, the subject may suffer from early cognitive impairment (MCI) (e.g., loss of short-term memory, difficulty in expressing or understanding abstract things, mood or behavior volatility, difficulty in learning new things and following complex instructions, decreased judgment and / or basic self-care requiring reminders from others), moderate cognitive impairment (e.g., confusion of long-term memory and reality memory, inability to express one's meaning, behavioral personality changes or emotional instability and / or requiring others to assist in self-care) or severe cognitive impairment (e.g., memory impairment, physical activity and mental state decline, inability to express or communicate effectively, inability to take care of oneself and / or biological clock confusion). In the present application, the subject may suffer from a disease that can cause the cognitive impairment to be induced. For example, the subject may suffer from Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). In the present application, the subject may be in the elderly stage. For example, the subject has shown cognitive impairment caused by normal aging. For example, the subject has shown symptoms of early cognitive impairment (MCI). For example, the subject has shown symptoms of a neurodegenerative disease (e.g., Alzheimer's disease). Without intending to be bound by any theory, the following embodiments are merely intended to illustrate various technical solutions of the present invention. It is not intended to limit the scope of the invention of this application. Example Example 1 Polypeptide binding to ATP6V1B2 protein This example illustrates that the polypeptide described in this application, the fusion polypeptide described in this application, and the ATP6V1B2 binder described in this application can bind to the ATP6V1B2 protein, and the binding can be detected by immunoprecipitation. The expression plasmids of hATP6V1B2, QD202 (SEQ ID NO.1), point mutation QD202 (D15A), point mutation QD202 (V16A) (SEQ ID NO.1), point mutation QD202 (P13A), and point mutation QD202 (V14A) were constructed respectively, and the specific sequences are shown in Table 1. hATP6V1B2 was transfected simultaneously with QD202, point mutation QD202 (D15A), point mutation QD202 (V16A), point mutation QD202 (P13A), and point mutation QD202 (V14A) expression plasmids in HEK 293, and cell proteins were extracted 48 hours after transfection. Table 1: Plasmid sequences Use Pierce RIPA lysis buffer for protein extraction. Take the cells in a 60mm culture dish as an example, add 500μL of Pierce RIPA lysis buffer containing protease inhibitors, use a cell scraper to collect the cells and transfer them to a clean 1.5mL EP tube. After mixing on a rotary mixer at 4℃ for 1 hour, centrifuge at 4℃, 13,000rpm for 10 minutes to remove cell debris. hATP6V1B2 was divided into 4 equal parts and mixed with the cell lysates transfected with QD202, point mutation QD202 (P13A), point mutation QD202 (V14A), point mutation QD202 (D15A), and point mutation QD202 (V16A), respectively. 30 μL of supernatant was added with 10 μL 4× loading buffer, boiled at 100°C for 5 minutes and then stored in a freezer at -20°C. 2 μL of antibody (Anti-GFP, Roche, 11814460001) was added to the remaining 470 μL of protein lysate and mixed on a 4°C rotary mixer overnight, about 16-18 hours. Take 30μL Protein G agarose beads (Roche, 11243233001) in an EP tube, wash three times with Pierce RIPA lysis buffer to remove the interference of the original storage solution, add the protein incubated with the antibody overnight to the agarose beads, mix and incubate at 4℃ for 2 hours to allow the antibody and protein to fully bind. Centrifuge at 4000rpm for 1 minute, remove the supernatant, add 600μL Pierce RIPA lysis buffer, gently flip, centrifuge and take the supernatant, repeat the above steps three times to wash the non-specifically bound protein. Finally, add 30μL 1× loading buffer, mix and heat at 60℃ for 20 minutes to denature the protein and store at -20℃. Detect the protein by western blot method (Myc-Tag (9B11) Mouse mAb, CST, 2276S; Anti-GFP, Roche, 11814460001). hATP6V1B2 was respectively combined with QD202, point mutation QD202(P13A), point mutation QD202(V14A), point mutation QD202(D15A), and point mutation QD202(V16A) expression plasmids in HEK cells 293, and the immunoprecipitation method showed that agarose beads could bind hATP6V1B2 with Myc tag to QD202, and could also bind to QD202 with aspartic acid mutated to alanine at position 15 (D15A), QD202 with proline mutated to alanine at position 13 (P13A) and QD202 with valine mutated to alanine at position 14 (V14A), but the binding to QD202 with valine mutated to alanine at position 16 (V16A) was weakened. It is speculated that valine 16 on QD202 is one of the important amino acids for the binding of hATP6V1B2 to QD202, and proline 13, valine 14 and aspartic acid 15 can be replaced by alanine, as shown in Figures 1A and 1B. Example 2 Biological Activity Test of Polypeptide 2.1 This example illustrates that the polypeptide described in this application, the fusion polypeptide described in this application, and the ATP6V1B2 binder described in this application can increase the spontaneous release of excitatory synaptic transmitters from neurons and can increase the frequency of the release of excitatory postsynaptic currents. After intraperitoneal injection of 20% ulose 0.1-0.15ml anesthesia, 2-3 month old C57 mice were quickly decapitated and the brain tissue was removed and placed in artificial cerebrospinal fluid (ACSF) mixed with ice water in advance (95% O2 and 5% CO2) for 2 minutes. The ACSF formula is as follows: NaCl 11.7mM, KCl 0.36mM, NaH2PO4 0.12mM, CaCl2 0.25mM, MgCl2 0.12mM, NaHCO3 25mM, glucose 11mM. 350mm hippocampal coronal slices were cut using a vibrating slicer. The hippocampal slices were placed in ACSF at room temperature for more than 30 minutes for recovery, and then the slices were placed in a recording tank and continuously perfused with ACSF with mixed gas at a rate of 2-2.5 ml / min. Under an Olympus BX51 upright microscope, the hippocampal CA1 pyramidal neurons were blindly ligated and sealed, and whole-cell patch clamp recording was performed using an Axon700B amplifier and a 1550B digital-to-analog converter. The spontaneous excitatory postsynaptic current (sEPSC) of the pyramidal neurons was recorded by voltage clamp under a clamping voltage of -70 mV, and the sEPSC was recorded 5 minutes after the administration of 5 μM of the polypeptide described in the present application, the fusion polypeptide described in the present application, or the ATP6V1B2 binder described in the present application, and then the ACSF was perfused for 10 minutes. The recorded data were analyzed using Minianalysis software. The effect of the polypeptide described in this application, the fusion polypeptide described in this application or the ATP6V1B2 binder described in this application on spontaneous excitatory postsynaptic currents (sEPSC) was recorded in hippocampal slices. The results are shown in Figure 2. The polypeptide described in this application, the fusion polypeptide described in this application or the ATP6V1B2 binder described in this application significantly enhanced the frequency of sEPSC, but had no significant effect on the amplitude of sEPSC. In addition, SS8 (whose amino acid sequence is shown in SEQ ID NO.54) has a stronger effect on enhancing the frequency of sEPSC than QD202 (whose amino acid sequence is shown in SEQ ID NO.1). 2.2 This example illustrates that the polypeptides described in this application, the fusion polypeptides described in this application and / or the ATP6V1B2 binders described in this application can enter cells and enhance lysosomal acidity. Vesicular proton pumps play an important role in the acidification of lysosomes. As an important subunit structure of vesicular proton pumps, ATP6V1B2 protein also plays an important role in the acidification of cell lysosomes. Therefore, this example functionally verifies the binding and regulation between the polypeptides described in this application, the fusion polypeptides described in this application or the ATP6V1B2 binders described in this application and the ATP6V1B2 protein by detecting the effects of the polypeptides described in this application, the fusion polypeptides described in this application or the ATP6V1B2 binders described in this application on the acidity of HEK293 cell lysosomes. The experimental materials and reagents used in this example are shown in the following table: LysoSensor TM The staining of Green DND-189 lysosomal green fluorescent probe is acidophilic and can be accumulated in acidic organelles through protonation. Its fluorescence intensity is pH-dependent (acidophilic) and increases with the degree of acidification of the organelles. The specific steps are as follows: HEK293 cells are inoculated in a 35mm glass-bottomed confocal culture dish, cultured in DMEM high-glucose medium, and grown to a density of 70-80% at 37°C and 5% carbon dioxide content. The polypeptide described in the present application (e.g., SS8) labeled with different concentrations of rhodamine was added to the cultured HEK-293 cells and incubated for different time points such as 2h, 4h, and 6h. The localization of the rhodamine fluorescence signal in the HEK-293 cells was observed under a fluorescence microscope. The results showed that the polypeptide described in the present application, the fusion polypeptide described in the present application and / or the ATP6V1B2 binder described in the present application were able to enter the cells. A drug-containing cell culture medium with a final DMSO concentration of 0.1% was prepared, and the drug concentrations were 1 μM V-ATPase inhibitor Bafilomycin A1 and different concentrations of the polypeptide / fusion polypeptide / ATP6V1B2 binder described in the present application (e.g., 5 μM, 20 μM). The culture medium was discarded, and a drug-containing culture medium or a blank control culture medium was added. The culture medium was incubated for 3 hours at 37°C and 5% carbon dioxide content. The culture medium was aspirated, washed once with PBS, and a probe-containing cell culture medium preheated at 37°C was added. The cells were incubated for 30 minutes in a growth state, and the staining solution was replaced with a fresh culture medium and observed under a fluorescence microscope. 5-6 field images were collected for each dish of cells, and the average fluorescence intensity of the images was analyzed using ImageJ software. A total of 3 parallel experiments were performed. The results showed that the fluorescence intensity of the lysosomes in the cell lysosomes treated with the vesicular proton pump inhibitor Bafilomycin A1 was significantly weaker than that in the untreated group. This indicates that inhibition of the vesicular proton pump can reduce lysosomal acidity, and the fluorescence intensity of the cell lysosomes in the group treated with the polypeptide described in this application, the fusion polypeptide described in this application, and / or the ATP6V1B2 binder described in this application is stronger than that in the untreated group, indicating that the cell lysosomal acidity is enhanced. This indicates that the polypeptide described in this application, the fusion polypeptide described in this application, and / or the ATP6V1B2 binder described in this application activates the function of the lysosomal vesicular proton pump by binding to the ATP6V1B2 protein, thereby increasing the lysosomal acidity. 2.3 This example illustrates that the polypeptide described in this application, the fusion polypeptide described in this application, and the ATP6V1B2 binder described in this application can enhance the H+ ion influx mediated by the vesicle-type proton pump on the lysosomal membrane. Whole lysosomal patch clamp electrophysiological recordings were performed using isolated lysosomes. In the presence of ATP, the current changes caused by the H+ ion influx mediated by the vesicular proton pump were recorded. Different concentrations of the polypeptide described in this application (e.g., SS8) were added, and its enhancement effect on the H+ ion current mediated by the vesicular proton pump was recorded, and compared with the effect of QD202 at the same concentration. The results show that the polypeptide described in this application, the fusion polypeptide described in this application, and the ATP6V1B2 binder described in this application can enhance the H+ ion influx mediated by the vesicular proton pump on the lysosomal membrane. Example 3 The improvement of learning ability by polypeptides. Example 3 Effect of polypeptide on improving learning ability This example illustrates that the polypeptide described in the present application, the fusion polypeptide described in the present application, and the ATP6V1B2 binder described in the present application have an improving effect on learning ability, including memory ability and cognitive ability. Novel object recognition test Novel object recognition refers to the behavioral test protocol described in Leger, M., et al. Object recognition test in mice. Nat Protoc. 8, 2531-2537 (2013), and an open field box (40×40×35 cm made of blue opaque plastic) was used for the novel object recognition test. On the first day, the mice were placed in the open field box for 10 minutes. On the second day, each mouse was gently placed in the center of the box, and two similar objects (No. 1 batteries) were placed in the central area, allowing them to explore freely for 10 minutes, and then the mice were returned to their cages. After 3 hours, the mice were returned to the box again (one battery was replaced with a 10 cm high puppet toy) for 10 minutes for memory retention test. The video was analyzed with Etho Vision XT 14 software to record the time taken by the mice to explore new / old objects. The discrimination index was calculated as (Tnovel-Tfamliar) / (Tnovel+Tfamiliar). Morris water maze test Morris water maze refers to the experimental scheme recorded by Qing-Feng Wu et al. in Fibroblast growth factor 13is a microtubule-stabilizing protein regulating neuronal polarization and migration. Cell. 149, 1549-1564 (2012). The test was carried out in a room with a fixed environment, in a circular pool filled with water (120 cm in diameter, 30 cm in depth, made opaque by adding titanium dioxide, and maintained at 21±1°C). The experiment was divided into an adaptation period (1 day), a training period (5-6 days) and a test period (1 day). Adaptation period: The platform was placed 0.5 cm above the water surface to guide the mice to the platform. Training day: The platform was placed 0.5 cm underwater and the mice were trained to find the platform. When the mouse reached the platform, the timing was stopped. If the mouse did not reach the platform within 1 minute, it was guided to the platform and stayed on the platform for 30s. Training was conducted 4 times a day (8:00-16:00), with mice being placed in different water entry points each time, with at least 30 min between each training session, for a total of 6 days, with the order of water entry points being different each day. Experimental day: The experiment was conducted 24 hours after the end of the training day. The platform was removed, and the mice were placed in the water from a water entry point that they had not trained for, and the video was recorded for 1 minute. The video was analyzed using Etho Vision XT 14 software, and the parameters recorded included the escape latency to enter the target quadrant, the number of times the platform was crossed, and the time spent in the target quadrant. The foregoing detailed description is provided by way of explanation and example, and is not intended to limit the scope of the appended claims. Various changes to the embodiments currently listed in this application are obvious to those of ordinary skill in the art and are retained within the scope of the appended claims and their equivalents.

Claims

1. A binding agent that binds to ATP6V1B2 and / or a functionally active fragment thereof.

2. The binding agent according to claim 1, wherein the ATP6V1B2 and / or its functionally active fragments are derived from mammals.

3. The binding agent according to any one of claims 1-2, wherein the ATP6V1B2 or a functionally active fragment thereof is derived from human or mouse. 4 . The binding agent according to any one of claims 1 to 3 , wherein the ATP6V1B2 comprises the amino acid sequence shown in SEQ ID NO: 8 or 16.

5. The binding agent according to any one of claims 1 to 4, wherein the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO:

5.

6. The binding agent according to any one of claims 1-5, wherein the functionally active fragment of ATP6V1B2 has the ability to specifically bind to the amino acid sequence shown in SEQ ID NO.

5.

7. The binding agent according to any one of claims 1 to 6, wherein the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the human ATP6V1B2 protein.

8. The binding agent according to any one of claims 1 to 7, wherein the functionally active fragment of ATP6V1B2 comprises at least a portion of the amino acid sequence from position 288 to position 512 of the mouse ATP6V1B2 protein.

9. The binding agent according to any one of claims 1-8, wherein the functionally active fragment of ATP6V1B2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 10-11. 10 . The binding agent according to any one of claims 1 to 9 , wherein the ATP6V1B2 comprises an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO. 9 or 17.

11. The binding agent according to any one of claims 1 to 10, which is capable of modulating proton pump activity and / or function.

12. The binding agent according to any one of claims 1 to 11, which is capable of increasing the expression level and / or activity of a proton pump-related protein in a subject.

13. The binding agent according to claim 12, wherein the expression level of the proton pump-related protein is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining and mass spectrometry.

14. The binding agent according to any one of claims 12-13, wherein the expression level of the proton pump-associated protein is measured by utilizing a substance selected from the following group: a primer capable of specifically amplifying a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a gene encoding a proton pump-associated protein, a nucleic acid molecule that specifically binds to a proton pump-associated protein, a small molecule that specifically binds to a proton pump-associated protein, a probe that specifically binds to a proton pump-associated protein, and a polypeptide that specifically binds to a proton pump-associated protein.

15. The binding agent according to any one of claims 1 to 14, which is capable of modulating the expression level and / or activity of the ATP6V1B2.

16. The binding agent according to any one of claims 1 to 15, which is capable of increasing the expression level and / or activity of ATP6V1B2 in a subject. 17 . The binding agent according to any one of claims 15 to 16 , wherein the expression level of ATP6V1B2 comprises the expression level of the ATP6V1B2 gene, the transcription level of the ATP6V1B2 gene and / or the expression level of the ATP6V1B2 protein.

18. The binding agent of any one of claims 15-17, wherein the increase comprises an increase in the expression level and / or activity of the ATP6V1B2 by at least about 10% compared to the expression level and / or activity of native ATP6V1B2 in the subject.

19. The binding agent of any one of claims 15-18, wherein the expression level of ATP6V1B2 is measured by performing an assay selected from the group consisting of qPCR, qRT-PCR, hybridization analysis, Northern blotting, dot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, and mass spectrometry.

20. The binding agent according to any one of claims 15-19, wherein the expression level of ATP6V1B2 is measured by using a substance selected from the following group: a primer capable of specifically amplifying the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 gene, a nucleic acid molecule that specifically binds to the ATP6V1B2 protein, a small molecule that specifically binds to the ATP6V1B2 protein, a probe that specifically binds to the ATP6V1B2 protein, and a polypeptide that specifically binds to the ATP6V1B2 protein.

21. The binding agent according to any one of claims 1 to 20, which is capable of increasing neuronal synaptic transmitter release.

22. The binding agent of claim 21, wherein the increase comprises an increase of at least about 10% compared to the level of native neuronal synaptic transmitter release in the subject.

23. The binding agent according to any one of claims 15 to 22, which increases the firing frequency of excitatory postsynaptic currents.

24. The binding agent of claim 23, wherein the increase comprises an increase of at least about 10% compared to the level of native excitatory postsynaptic current firing frequency in the subject.

25. The binding agent of any one of claims 1-24, comprising a protein and / or a polypeptide.

26. The binding agent according to claim 25, comprising the amino acid sequence shown in SEQ ID NO: 33 and / or a variant thereof, wherein X is any amino acid.

27. The binding agent according to any one of claims 25-26, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 30-32 and / or a variant thereof, wherein X is any amino acid.

28. The binding agent according to any one of claims 25 to 27, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 27 to 29 and / or a variant thereof, wherein X is any amino acid.

29. The binding agent according to any one of claims 25 to 28, comprising the amino acid sequence shown in SEQ ID NOs: 19 to 26 and / or variants thereof.

30. The binding agent of any one of claims 1-29, comprising a multimer.

31. The binding agent of claim 30, wherein the multimer comprises a homodimer.

32. The binding agent according to any one of claims 25 to 31, wherein the cysteine ​​in its amino acid sequence does not have a thiol-blocking modification.

33. The binding agent according to any one of claims 25 to 32, wherein the serine in its amino acid sequence does not have phosphorylation modification.

34. The binding agent of any one of claims 1-33, comprising a fusion protein and / or a fusion polypeptide.

35. The binding agent of any one of claims 34, wherein the fusion protein and / or fusion polypeptide comprises a molecule capable of being transported across the blood-brain barrier to the brain.

36. The binding agent of claim 35, wherein the molecule capable of being transported across the blood-brain barrier to the brain comprises a polypeptide.

37. The binding agent of any one of claims 35-36, wherein the molecule capable of being transported across the blood-brain barrier to the brain comprises a cell-penetrating peptide.

38. The binding agent of claim 37, wherein the cell-penetrating peptide comprises the amino acid sequence of SEQ ID NO:

34.

39. The binding agent according to any one of claims 34 to 38, comprising the amino acid sequence as shown in SEQ ID NO: 48, wherein X is any amino acid.

40. The binding agent according to any one of claims 34-39, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 45-47, wherein X is any amino acid.

41. The binding agent according to any one of claims 34 to 40, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 42 to 44 and / or a variant thereof, wherein X is any amino acid.

42. The binding agent according to any one of claims 34-41, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 35-41 and / or a variant thereof.

43. An isolated polypeptide comprising the amino acid sequence as shown in SEQ ID NO: 33 and / or a variant thereof, wherein X is any amino acid.

44. The polypeptide according to claim 43, comprising the amino acid sequence shown in SEQ ID NO: 30-32 and / or variants thereof, wherein X is any amino acid.

45. The polypeptide according to any one of claims 43-44, comprising an amino acid sequence as shown in any one of SEQ ID NOs: 27-29 and / or a variant thereof, wherein X is any amino acid.

46. ​​The polypeptide according to any one of claims 43 to 45, comprising the amino acid sequence shown in SEQ ID NO: 19 to 26 and / or variants thereof.

47. A fusion polypeptide comprising the polypeptide of any one of claims 43-46.

48. The fusion polypeptide of claim 47, further comprising a molecule capable of being transported across the blood-brain barrier to the brain.

49. The fusion polypeptide of claim 48, wherein the molecule transported across the blood-brain barrier to the brain comprises a polypeptide.

50. The fusion polypeptide according to any one of claims 48-49, wherein the molecule capable of being transported across the blood-brain barrier to the brain comprises a cell-penetrating peptide.

51. The fusion polypeptide according to any one of claims 47 to 50, wherein the cell-penetrating peptide comprises the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof.

52. The fusion polypeptide according to any one of claims 47 to 51, comprising the amino acid sequence as shown in SEQ ID NO: 48 and / or a variant thereof, wherein X is any amino acid.

53. The fusion polypeptide according to any one of claims 47 to 52, comprising an amino acid sequence as described in any one of SEQ ID NOs: 45 to 47 and / or variants thereof, wherein X is any amino acid.

54. The fusion polypeptide according to any one of claims 47 to 53, comprising an amino acid sequence as described in any one of SEQ ID NOs: 42 to 44 and / or variants thereof, wherein X is any amino acid.

55. The fusion polypeptide according to any one of claims 47 to 54, comprising the amino acid sequence of any one of SEQ ID NOs: 35 to 41 and / or variants thereof.

56. An immunoconjugate comprising the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, and / or the fusion polypeptide of any one of claims 47-55.

57. A nucleic acid molecule encoding the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, and / or the fusion polypeptide of any one of claims 47-55.

58. A vector comprising the nucleic acid molecule of claim 57.

59. A cell comprising the binding agent of any one of claims 1-42, the polypeptide or variant thereof of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57 and / or the vector of claim 58.

60. A pharmaceutical combination comprising the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57, the vector of claim 58 and / or the cell of claim 59.

61. A pharmaceutical composition comprising the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57, the vector of claim 58 and / or the cell of claim 59, and optionally a pharmaceutically acceptable carrier.

62. A kit comprising the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57, the vector of claim 58, the cell of claim 59, the pharmaceutical combination of claim 60 and / or the pharmaceutical composition of claim 61.

63. Use of the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57, the vector of claim 58, the cell of claim 59, the drug combination of claim 60 and / or the pharmaceutical composition of claim 61 in the preparation of a kit.

64. Use of the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57, the vector of claim 58, the cell of claim 59, the drug combination of claim 60 and / or the pharmaceutical composition of claim 61 in detecting ATP6V1B2.

65. A method for detecting ATP6V1B2 in a sample, comprising administering the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57, the vector of claim 58, the cell of claim 59, the pharmaceutical combination of claim 60, the pharmaceutical composition of claim 61 and / or the kit of claim 62.

66. Use of the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57, the vector of claim 58, the cell of claim 59, the drug combination of claim 60 and / or the pharmaceutical composition of claim 61 in the preparation of an agent for improving learning ability, treating cognitive disorders and / or treating neurodegenerative diseases.

67. The use according to claim 66, wherein the learning ability comprises cognitive ability, motor ability, memory ability and / or spatial exploration ability.

68. The use according to any one of claims 66-67, wherein the improvement in learning ability comprises an improvement in the assessment score of the subject's learning ability by at least about 50% compared to the subject's original assessment score of learning ability.

69. The use according to any one of claims 66-68, wherein the assessment score of the learning ability is measured by performing a test selected from the group consisting of a novel object recognition test and a water maze test.

70. The use according to claim 69, wherein the novel object recognition test evaluates the cognitive ability, motor ability and / or spatial exploration ability.

71. The use according to any one of claims 69-70, wherein the water maze test evaluates the memory ability, motor ability and / or spatial exploration ability.

72. The use according to any one of claims 69-71, wherein the cognitive impairment comprises early cognitive impairment (MCI), moderate cognitive impairment and severe cognitive impairment.

73. The use according to any one of claims 69-72, wherein the cognitive impairment comprises cognitive impairment caused by normal aging, Lewis body dementia (LBD), frontotemporal dementia and / or vascular dementia.

74. The use according to any one of claims 69-73, wherein the inducing disease of cognitive impairment comprises Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD).

75. The use according to any one of claims 69-74, wherein the neurodegenerative disease comprises an acute neurodegenerative disease and a chronic neurodegenerative disease.

76. The method of any one of claims 69-75, wherein the neurodegenerative disease comprises a neurodegenerative disease caused by neuronal death and glial cell homeostasis, a neurodegenerative disease caused by aging, a neurodegenerative disease caused by affected CNS cell function, a neurodegenerative disease caused by abnormal intercellular communication, and / or a neurodegenerative disease caused by impaired cell motility.

77. The use according to any one of claims 69-76, wherein the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

78. The use of any one of claims 69-77, wherein the subject comprises a mammal.

79. The use according to any one of claims 69-78, wherein the subject comprises a human.

80. The use according to any one of claims 69-79, wherein the subject comprises a non-cognitive disorder patient and / or a non-neurodegenerative disease patient.

81. The use according to any one of claims 69-80, wherein the subject comprises a patient with a neurodegenerative disease and / or a patient with a cognitive disorder.

82. The use according to any one of claims 69-81, wherein the subject comprises an Alzheimer's disease patient.

83. The use according to any one of claims 69-82, wherein the subject is in the elderly stage.

84. The use according to any one of claims 69-83, wherein the agent is formulated for oral administration and / or injection.

85. The use according to any one of claims 69-84, wherein the agent is formulated for intravenous injection.

86. Use of the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate described in claim 56, the nucleic acid molecule described in claim 57, the vector described in claim 58, the cell described in claim 59, the drug combination described in claim 60 and / or the pharmaceutical composition described in claim 61 in improving learning ability, treating cognitive disorders and / or treating neurodegenerative diseases.

87. A method for improving learning ability, treating cognitive disorders and / or treating neurodegenerative diseases, comprising administering to a subject in need thereof the binding agent of any one of claims 1-42, the polypeptide of any one of claims 43-46, the fusion polypeptide of any one of claims 47-55, the immunoconjugate of claim 56, the nucleic acid molecule of claim 57, the vector of claim 58, the cell of claim 59, the drug combination of claim 60 and / or the pharmaceutical composition of claim 61.