DIR-binding agents and uses thereof

Abstract

A binding agent that binds to an intron retention cleavage product DIR and / or a functional fragment thereof of a DNA damage-induced transcript 4-like transcript and uses thereof.

Description

DIR binder and its use Technical Field The present application relates to the field of biomedicine, and specifically to a binding agent that binds to DIR and / or its functional fragments and its use in improving cognitive impairment. Background Art At present, the number of aging population in my country is increasing year by year. Due to the influence of factors such as decreased immunity and vascular sclerosis, the elderly are facing the troubles of various diseases. Among them, the incidence of Alzheimer's disease in the current elderly population cannot be ignored. Dementia patients are not only tortured by the disease themselves, but also put great pressure on their families. Therefore, it is extremely important to develop therapeutic drugs for Alzheimer's disease. During the years of research, more and more genes related to Alzheimer's disease have been reported, such as APP, PSEN1, etc. These gene mutations accelerate neuronal damage, thereby causing cognitive impairment. Drugs based on these targets, especially monoclonal antibody drugs targeting Aβ, have multiple R&D and production pipelines, and some drugs approved by the FDA have been launched this year. However, although this type of monoclonal antibody drug can effectively remove the accumulation of Aβ in the human brain, it is not ideal for improving patients' cognitive abilities. It can be seen that new methods to improve cognitive impairment are urgently needed. Summary of the invention The present application provides a novel method for improving cognitive impairment. In one aspect, the present application provides a binding agent that binds to the intron retained splicing product DIR and / or its functional fragment of a DNA damage-inducible transcript 4-like transcript. In certain embodiments, the DIR and / or its functional fragment are derived from a mammal. In certain embodiments, the DIR and / or its functional fragment are derived from primates. In certain embodiments, the DIR and / or its functional fragment are derived from human. In certain embodiments, the DIR comprises the amino acid sequence shown in SEQ ID NO:1. In certain embodiments, the functional fragment of DIR comprises an amino acid sequence encoded by a retained intron in DDIT4L. In certain embodiments, the functional fragment of DIR comprises an amino acid sequence as shown in any one of SEQ ID NOs: 4-5. Amino acid sequence. In certain embodiments, the binding agent is a protein and / or a polypeptide. In certain embodiments, the binding agent comprises the receptor subunit GluA1 of ionotropic glutamate receptors (AMPARs) and / or a fragment thereof. In certain embodiments, the GluA1 and / or fragments thereof are derived from mammals. In certain embodiments, the GluA1 and / or fragments thereof are derived from primates. In certain embodiments, the GluA1 and / or fragments thereof are of human origin. In certain embodiments, the GluA1 comprises the amino acid sequence shown in SEQ ID NO: 7 and / or its variants. In certain embodiments, the binding agent comprises the amino acid sequence shown at positions 198 to 205 of GluA1 and / or a functional variant thereof. In certain embodiments, the binding agent comprises the amino acid sequence shown in SEQ ID NO: 8 and / or a functional variant thereof. In certain embodiments, the binding agent is capable of regulating the expression level and / or biological activity of the intron retained splicing product DIR of the DNA damage-inducible transcript 4-like transcript and / or its functional fragments. In certain embodiments, the binding agent is capable of reducing the expression level and / or biological activity of the DIR and / or its functional fragment in a subject. In certain embodiments, the reduction comprises a reduction of at least about 10% in the expression level and / or biological activity of the DIR and / or its functional fragment compared to the original expression level and / or biological activity of the DIR and / or its functional fragment in the subject. In certain embodiments, the expression level includes the expression level of the gene encoding the DIR / or its functional fragment, the transcription level of the gene encoding the DIR / or its functional fragment and / or the expression level of the DIR / or its functional fragment. In certain embodiments, the functional fragment of the DIR retains at least a portion of the biological activity of the DIR. In certain embodiments, the biological activity comprises the ability to reduce the frequency of excitatory postsynaptic current (EPSC) and / or the ability to reduce the amplitude of EPSC. In certain embodiments, the reduction comprises administering the DIR and / or its functional fragment and / or a nucleic acid encoding the DIR and / or its functional fragment, thereby reducing the frequency of excitatory postsynaptic currents (EPSCs) in the subject and / or reducing the amplitude of EPSCs in the subject, compared to the biological activity of the original DIR and / or its functional fragment in the subject. In certain embodiments, the biological activity comprises affecting cognitive abilities. In certain embodiments, the biological activity comprises participation in a signaling pathway associated with Aβ deposition, and / or Involved in signaling pathways associated with Tau tangle generation. In certain embodiments, the biological activity comprises inducing Aβ deposition and / or amyloid plaque formation by gelsolin. In certain embodiments, the DIR and / or its functional fragment induces Aβ deposition and / or amyloid plaque formation by binding to gelsolin. In certain embodiments, the expression level of the DIR and / or its functional fragment is positively correlated with the expression level of Aβ. In another aspect, the present application provides an isolated polypeptide comprising the amino acid sequence shown in SEQ ID NO: 8 and / or its variants. In another aspect, the present application provides an immunoconjugate comprising the binding agent described herein and / or the polypeptide described herein. On the other hand, the present application provides a nucleic acid molecule encoding the binding agent described in the present application and / or the 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 described in the present application, the nucleic acid molecule described in the present application and / or the vector described in the present application. On the other hand, the present application provides a pharmaceutical composition comprising the binding agent described herein, the 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 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 and / or the pharmaceutical composition described in the present application. In certain embodiments, the kit is used to detect DIR in a sample. On the other hand, the present application provides a method for detecting DIR in a sample, the method comprising administering the binding agent described in the present application, the polypeptide molecule 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. On the other hand, the present application provides the use of the binding agent described in the present application, the 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 and / or the pharmaceutical composition described in the present application in the preparation of a kit. On the other hand, the present application provides the binding agent described in the present application, the 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 and / or the A pharmaceutical composition, use thereof in preparing an agent for preventing and / or treating a disease, wherein the disease includes cognitive impairment. On the other hand, the present application provides the use of the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein and / or the pharmaceutical composition described herein in the preparation of an agent for preventing and / or treating a disease, wherein the disease includes a neurodegenerative disease. On the other hand, the present application provides the use of the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the pharmaceutical composition described herein and / or the kit described herein in the preparation of a reagent for diagnosing and / or assessing a disease, wherein the disease includes cognitive impairment. On the other hand, the present application provides the use of the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the pharmaceutical composition described herein and / or the kit described herein in the preparation of a reagent for diagnosing and / or evaluating a disease, wherein the disease includes a neurodegenerative disease. 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 cognitive impairment comprises early cognitive impairment (MCI), mid-stage cognitive impairment and late stage cognitive impairment. In certain embodiments, the cognitive impairment comprises amnestic MCI with impairment of multiple cognitive domains (aMCI-m). 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 neurodegenerative disease comprises Alzheimer's disease. In certain embodiments, the neurodegenerative disease comprises early Alzheimer's disease, middle Alzheimer's disease and / or late Alzheimer's disease. In certain embodiments, the subject comprises a mammal. In certain embodiments, the subject comprises a human. 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. On the other hand, the present application provides a method for preventing and / or treating cognitive impairment, which comprises administering the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein and / or the pharmaceutical composition described herein to a subject in need thereof. On the other hand, the present application provides a method for preventing and / or treating neurodegenerative diseases, which comprises administering the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein and / or the pharmaceutical composition described herein to a subject in need thereof. On the other hand, the present application provides a method for diagnosing cognitive impairment and / or assessing cognitive impairment, which comprises using the binding agent described in the present application, the 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 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 method for diagnosing a neurodegenerative disease and / or evaluating a neurodegenerative disease, which comprises using the binding agent described in the present application, the 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 pharmaceutical composition described in the present application and / or the kit described in the present application. On the other hand, the present application provides the use of the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein and / or the pharmaceutical composition described herein in preventing and / or treating cognitive disorders. On the other hand, the present application provides the use of the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein and / or the pharmaceutical composition described herein in preventing and / or treating neurodegenerative diseases. On the other hand, the present application provides the use of the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the pharmaceutical composition described herein and / or the kit described herein in the diagnosis and / or assessment of cognitive disorders. On the other hand, the present application provides the use of the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the pharmaceutical composition described herein and / or the kit described herein in the diagnosis and / or assessment of neurodegenerative diseases. 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: Figures 1A-1D show the identification of DIR described in the present application. Figure 1A shows the formation of the human DDIT4L gene spliceosome described in the present application, wherein NS represents the normal spliceosome and IR represents the DIR formed by abnormal splicing. Figure 1B shows the mRNA identification results of DDIT4L and DIR. Figure 1C shows the results of Western Blot detection of DIR expression using DIR antibody. Figure 1D shows the results of Western Blot detection of DIR expression in blood samples using DIR antibody. FIG. 2 shows the effect of the functional fragment of DIR described in the present application on excitatory postsynaptic current. FIG3 is a schematic diagram showing the structure of the functional fragment of DIR described in the present application. FIG. 4 shows the biological functions of the DIR functional fragments described in the present application. Figures 5A-5I show that DIR induces Aβ deposition by binding to gelsolin. Figure 5A: DIR is present in thioflavin-s-positive plaques (arrows) in the hippocampus of AD patients (n=3). Scale bar = 50 μm. Figure 5B: In the lysate of HEK293T cells transfected with a Flag-DIR plasmid and supplemented with synthetic Aβ42, Aβ42 was found in the protein captured by the Flag antibody (n=3). Figure 5C: PLA experiments showed that DIR could not bind to Aβ in the hippocampus of AD patients. Scale bar = 50 μm. Figure 5D: Coomassie blue staining showed that in the lysate of U87MG cells transfected with a Flag-DIR plasmid, the DIR antibody could capture a protein with a molecular weight of approximately 85 kDa (n=3). Figure 5E: Mass spectrometry identified the top 8 molecules in the ~85 kDa size range. Gelsolin is the most abundant molecule among them. Fig. 5F: In the hippocampal lysate of DIR-knock-in mice, gelsolin was found in the proteins captured by DIR and Aβ antibodies (n=3). Fig. 5G: PLA experiments showed that gelsolin binds to Aβ (arrows) in the hippocampus of AD patients. Scale bar = 50μm. Fig. 5H: In the lysate of HEK293T cells expressing Flag-DIR, different doses of Aβ42 were added, gelsolin was found in the proteins captured by Flag antibody, and the binding level of the two increased in the high-dose Aβ42 group (10μg, n=3). Fig. 5I: In the mixture of gelsolin-his and synthetic Aβ42 or DIR(31-84), DIR(31-84) increased the insolubility of Aβ42 through gelsolin (n=3). Figures 6A-6D show that DIR does not directly bind to Aβ, but induces Aβ deposition. Figure 6A: Synthetic Aβ42 was added to the lysate of HEK293T cells transfected with DIR plasmid or DDIT4L, and then immunoprecipitation experiments were performed using myc antibodies. Only the lysate expressing DIR was able to precipitate Aβ (n=3). Figure 6B: Co-immunoprecipitation experiments were performed using synthetic DIR(31-84) and Aβ42, and the results showed that there was no direct interaction between the two (n=3). Figure 6C: In the lysate of HEK293T cells co-transfected with Flag-DIR and gelsolin-GFP plasmids, gelsolin-GFP was found in the protein captured by Flag antibody (n=3). Figure 6D: Synthetic Aβ42 or DIR(31-84) was added to the lysate of HEK293T cells, and DIR(31-84) increased the insolubility of Aβ42 through gelsolin (n=3). Figures 7A-7C show DIR-mediated Aβ plaque formation. Figure 7A: Synthetic human Aβ40 (100 μM) was added to the hippocampal slices of DIR-KI mice (n=3), and Thioflavin S-positive plaques (arrows) appeared after 6 h of incubation, and were co-labeled with DIR and gelsolin. Scale bar = 100 μm. Figure 7B: In AD patients (n=3), but not in controls (n=3), Thioflavin S-positive dense nuclear plaques were co-localized with DIR and gelsolin (arrows) in the DG region of the hippocampus. Scale bar = 50 μm. Figure 7C: DIR is present in Aβ- and Thioflavin S-positive plaques (arrows) in the hippocampus of AD patients (n=3). The Aβ-positive area is larger than the Thioflavin S- and DIR-positive signals. Scale bar = 50 μm. Figure 8 shows diffuse Aβ-positive, thioflavin s-negative plaques (indicated by arrows) without overlap with DIR and gelsolin in the dentate gyrus (DG) of the hippocampus in Alzheimer's disease patients (n=3), but not in control individuals (n=3). Scale bar = 50 μm. Figures 9A-9L show that plasma DIR is a potential biomarker for AD and aMCI. Figure 9A: Compared with cognitively normal controls (NC, n = 33), plasma DIR in patients with naMCI (n = 44), aMCI (n = 42) or AD (n = 31) gradually increased. **, p < 0.01, ***, p < 0.001. Figure 9B: Compared with NC (n = 33), plasma Aβ42 / Aβ40 in patients with naMCI (n = 44), aMCI (n = 42) or AD (n = 31) gradually decreased. *, p < 0.05, **, p < 0.01. Figure 9C: Compared with NC (n = 33), plasma pTau181 in patients with naMCI (n = 44), aMCI (n = 42) or AD (n = 31) gradually increased. *, p < 0.05, ***, p < 0.001. Figure 9D: Compared with the control group (n=33), there was no significant change in plasma tTau in patients with naMCI (n=44), aMCI (n=42), and AD (n=31). Figure 9E: Receiver operating characteristic (ROC) analysis of plasma DIR in patients with NC (n=33) and AD (n=31). Figure 9F: ROC analysis of plasma pta181 in NC (n=33) and AD (n=31). Figure 9G: ROC analysis of plasma Aβ42 / Aβ40 in NC (n=33) and AD (n=31). Figure 9H: ROC analysis of NC (n=33) and AD (n=31) combined with plasma DIR, pTau181 and Aβ42 / Aβ40 (red). ROC analysis of NC (n=33) and AD (n=31) combined with plasma pTau181 and Aβ42 / Aβ40 (blue). Figure 9I: ROC analysis of plasma DIR in NC (n=33) and aMCI (n=42). Figure 9J: ROC analysis of plasma pTau in NC (n=33) and aMCI (n=42). Figure 9K: ROC analysis of plasma Aβ42 / Aβ40 in NC (n=33) and aMCI (n=42). Figure 9L: ROC analysis of combined plasma DIR, pta181 and Aβ42 / Aβ40 in NC ROC analysis of NC (n=33) and aMCI (n=42) (red). ROC analysis of NC (n=33) and aMCI (n=42) combined with plasma pta181 and Aβ42 / Aβ40 (blue). Figures 10A-10B show ROC analysis of plasma tTau. Figure 10A: ROC analysis of plasma tTau in NC (n=33) and AD (n=31). Figure 10B: ROC analysis of plasma tTau in NC (n=33) and aMCI (n=42). Figures 11A-11E show the correlation analysis between plasma DIR and Aβ. Figure 11A: Plasma DIR of normal but current MCI patients (n=12) three years ago (follow-up of patients started in 2018 and ended in 2021). Plasma DIR concentrations in MCI patients were higher than in blood samples collected 3 years ago. Figure 11B: Plasma DIR was positively correlated with plasma Aβ40 in MCI and AD patients (n=117) and cognitively normal controls (n=33). Figure 11C: Three-dimensional visualization of amyloid 18F-AV-45 SUV in I or NC of AD / MC patients. The color bar represents the SUV index obtained from the amyloid 18F-AV-45 image. Plasma DIR values ​​in AD / MCI patients were associated with positive signals in the cortex, especially in the temporal lobe. Figure 11D: Plasma DIR was significantly increased in amyloid PET-positive individuals (n=11) compared with amyloid PET-negative individuals (n=26). ROC analysis of plasma DIR in amyloid PET-positive individuals (n=11) and amyloid PET-negative individuals (n=26). **, p<0.01. Figure 11E: Model of DIR-induced amyloid plaque deposition and blood secretion. Under pathological conditions, hypoxia leads to abnormal intron retention, which causes the translation of DIR protein. Aβ is produced by the proteolytic process of amyloid precursor protein (APP) and has a direct binding to gelsolin. DIR causes Aβ deposition by binding to gelsolin, ultimately forming amyloid plaques in the brain. DIR can also be released into the blood system. Figures 12A-12B show the correlation between plasma DIR and Aβ42, and quantitative analysis of the SUV value of Aβ-PET. Figure 12A: Plasma DIR is positively correlated with plasma Aβ42 in MCI and AD patients (n=117) and cognitively normal controls (n=33). Figure 12B: Quantitative analysis of SUV values ​​in AD / MCI patients or NC. *, p<0.05. Figures 13A-13B show that GluA1 is a binding target of DIR as described in the present application. Figure 13A shows the results of a co-IP experiment of brain tissues of wild-type mice and DIR knock-in mice. Figure 13B shows that mass spectrometry analysis of the specific binding band of DIR revealed that GluA1 is a binding target of DIR. Figures 14A-14B show that GluA1 described in the present application can bind to DIR. Figure 14A shows that a co-IP experiment was performed using brain tissues of wild-type mice and DIR knock-in mice, and the experimental results showed that DIR can bind to GluA1. Figure 14B shows that DIR and GluA1 were exogenously expressed in HEK293 cells and a co-IP experiment was performed, and the results also showed that DIR can bind to GluA1. Figures 15A-15C show that the fragments derived from GluA1 described in the present application can bind to DIR. Figure 15A shows that GluA1 was found to bind to DIR by computer simulation. R198-E205 is the binding site for DIR, and GluA1 C204 Figure 15B shows that adding a short peptide of GluA1 (R198-E205) at a final concentration of 10uM to the cell lysate of co-transfected GluA1 and DIR can effectively block the binding between GluA1 and DIR. Figure 15C shows that in the case of co-transfected GluA1 Or point mutations in GluA1 (GluA1 C204A ) and DIR cell lysates were used for Co-IP experiments and found that GluA1 C204A Binding to DIR was weakened. FIG. 16 shows that the polypeptide fragment derived from GluA1 described in the present application can reverse the inhibitory effect of sEPSC induced by DIR. FIG. 17 shows that administration of the polypeptide fragment derived from GluA1 described in the present application can improve the learning ability of mice. 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 "DDIT4L" generally refers to DNA damage-inducible transcript 4-like, which may also be referred to as REDD2 / RTP801L. Studies have found that DDIT4L may be associated with cardiac dysfunction. It may also be used to treat gliomas. For example, the accession number of the human DDIT4L gene in GenBank is 115265; the accession number of the human DDIT4L protein in GenBank is NP_660287.1. In the present application, the term "DIR" generally refers to the intron retention splicing product of DDIT4L. The splicing reaction of DDIT4L can be seen in Figure 1. In the present application, the amino acid sequence of DIR can be shown as SEQ ID NO:1. 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. In the present application, the term "GluA1" may also be referred to as GIRA1 (glutamate ionotropic receptor AMPA type subunit 1), which generally refers to one of the four subtypes of ionotropic glutamate receptors (AMPARs). GluA1 is related to neuronal synaptic transmission and the release of action potentials, and is also closely related to the occurrence and development of AD. For example, the accession number of the human GluA1 gene in GenBank may be 2890; the accession number of the human GluA1 protein in Uniprot may be P42261. In the present application, the amino acid sequence of the GluA1 may be as shown in SEQ ID NO:7. In the present application, the "variant" and / or "functional variant" may be, for example, a protein or polypeptide in which one or more amino acids have been substituted, deleted or added in the amino acid sequence of the protein and / or the polypeptide (e.g., a binding agent that specifically binds to DIR or a fragment thereof). For example, the variant may comprise a protein or polypeptide that has been subjected to amino acid changes by at least 1, 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 retain the amino acid sequence of the protein or polypeptide prior to the change (e.g., substitution, deletion or addition). The biological properties of the protein or the polypeptide. For example, the functional variant can maintain at least 60%, 70%, 80%, 90%, or 100% of the biological activity (e.g., the ability to specifically bind to DIR) of the protein or the polypeptide before the change. For example, the substitution can be a conservative substitution. For example, the variant can also be a polypeptide covering its functionally active fragments, not limited to the polypeptide containing the functionally active fragment of the protein produced after processing and / or modification occurring in the 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 polypeptide (e.g., a binding agent or fragment thereof that specifically binds to DIR). In the present application, described homology generally refers to the similarity, similarity or association between two or more sequences. " sequence homology percentage ratio " can be calculated 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, I) 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 positions in two sequences 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 be realized in a variety of ways known in the art, for example, using 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 terms "polypeptide molecule" and "polypeptide" and "peptide" are used interchangeably and generally refer to polymers of amino acid residues. The term "fusion protein" generally refers to a polypeptide having at least two parts covalently linked together. Each part can be a polypeptide with different properties. The property can be a biological property, such as in vitro or in vivo activity. The property can also be a simple chemical or physical property, such as binding to a target molecule, catalysis of a reaction, etc. The two parts can be directly connected by a single peptide bond or by a peptide linker. In this application, the term "isolated" generally refers to an artificial method obtained from a natural state. For example, a certain unisolated polynucleotide or polypeptide naturally exists in a living animal, and a highly purified polynucleotide or polypeptide isolated from this natural state 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 delivery vehicle into which a polynucleotide encoding a protein can be inserted and the protein can be expressed. A vector can transform, transduce or transfect a host cell so that the genetic material elements it carries are expressed in the host cell. A vector may contain multiple elements that control expression. In addition, a vector may also contain a replication initiation site. A 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 used. Physiologically acceptable carriers may include suitable substances. Pharmaceutically acceptable carriers and vectors used to insert nucleic acids in genetic engineering are generally not the same substance. 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. The term "expression level" generally refers to the protein, RNA or mRNA level of a specific related gene. The expression level of a specific related gene (e.g., human DDIT4L gene) can be determined by any method known in the art. In the present application, "expression" generally refers to the process of converting the information encoded by a gene into a structure present in a cell and operating in the 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 a protein / nucleic acid separated from a sample. The term "activity" generally refers to any activity associated with a particular protein. In the present application, the activity may include any activity associated with, for example, a DIR 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 the binding of a protein to a receptor, for example, the binding may produce a measurable downstream effect. In the present application, the activity may include any activity that would be attributed to the protein by a person skilled in the art. The term "cognitive impairment" generally refers to a progressive loss (including neuronal death) or related diseases and conditions that are believed to be or are involved in neuronal structure and / or function. For example, the characteristics of the cognitive impairment may include damage to cognition (e.g., memory, attention, perception and / or thinking). These disorders may include pathogen-induced cognitive dysfunction, such as HIV-related cognitive dysfunction and Lyme disease-related cognitive dysfunction. Examples of cognitive impairment may include Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), autism, early cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and / or age-related memory impairment (AAMI). 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 balance. 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. The term "Alzheimer's disease" usually refers to early-onset dementia or senile dementia, a neurodegenerative disease that progresses slowly and 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., getting lost easily), emotional instability, loss of motivation, inability to take care of oneself, and behavioral problems. The true cause of Alzheimer's disease remains unknown. Its progression may be related to the deposition of fibrillar amyloid plaques and Tau proteins in the brain. There is currently no treatment that can stop or reverse the course of the disease, but only a few methods may temporarily relieve or improve symptoms. The term "Alzheimer's disease" can be used interchangeably with the term "Alzheimer's disease" in this application. The Alzheimer's disease can include early Alzheimer's disease, mid-Alzheimer's disease and / or late Alzheimer's disease. For example, the learning and memory disorders of the early Alzheimer's disease patients will become more and more obvious, and in some cases, there will be language disorders, execution disorders, cognitive disorders (anognosia) and / or skill execution disorders (apraxia). For example, the mid-Alzheimer's disease patients will lose the ability to live independently and may not be able to carry out most of the daily activities (in some cases, they may suffer from anomia, aphasia, and / or agnosia). For example, the late Alzheimer's disease patients may rely on caregivers in the late stage. For example, the language ability may be completely lost. For example, they may not be able to eat on their own. The term "early cognitive impairment (MCI)" generally refers to an intermediate clinical state between normal cognition and cognitive impairment. In some cases, the MCI may include cognitive impairment that meets the criteria for dementia but exceeds normal aging. MCI is diverse in clinical manifestations, causes, prognosis, and prevalence. In some cases, MCI may be a pathological stage of Alzheimer's disease. Certain forms of cognitive impairment can be considered early manifestations of neurodegenerative diseases, which will eventually lead to dementia. In some cases, the MCI may include a subtype selected from the following group: aMCI-s: amnestic MCI with a single cognitive domain impairment; aMCI-m: amnestic MCI with multiple cognitive domain impairment; naMCI-s: non-amnestic MCI with a single cognitive domain impairment; and naMCI-m: non-amnestic MCI with multiple cognitive domain impairment. The term "cognitive impairment due to normal aging" generally refers to cognitive impairment due to normal aging. For example, cognitive impairment due to normal aging can manifest as: memory loss, confusion about the location of familiar places, taking longer than usual to complete daily tasks, or changes in mood and personality. The term "lewy body dementia (LBD)" usually refers to Lewy Body Detmentia. 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. People with Lewy bodies in the brain can also have plaques and tangles associated with Alzheimer's disease. The term "frontotemporal dementia" usually refers to Pick's disease, a rare, progressive disorder in which the tau protein affects only the frontal and temporal lobes of the brain. People with frontotemporal dementia have difficulty with higher-level reasoning, expressive language, speech perception, and memory formation. The frontal and temporal lobes of the brain can shrink over time in people with frontotemporal dementia. The term "vascular dementia" generally refers to problems with reasoning, judgment, and memory caused by impaired blood flow to the brain. For example, vascular dementia can include dementia caused by factors that increase risk of heart disease and stroke, such as high blood pressure and high cholesterol. The term "multi-infarct type" generally refers to small noncortical infarcts caused by occlusion of a single perforator of a large cerebral artery. The multiple infarction type may be a special type of cerebral infarction, also known as ischemic stroke. The multiple infarction type may be manifested as hemisensory disturbance, aphasia, dysarthria, slow movements, and clumsiness (especially fine movements such as writing are more difficult). The term "Parkinson's disease" generally refers to a progressive neurodegenerative disease. The clinical features of Parkinson's disease (PD) may include motor symptoms (e.g., tremor, bradykinesia, rigidity, and postural instability), as well as neuropsychiatric 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. The term "CJD" usually 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 neurological deterioration (such as sensory abnormalities, language disorders and aphasia). 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, dysesthesia, or coordination disorders. The term "amyotrophic lateral sclerosis (ALS)" usually refers to Lou Gehrig's disease and 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 sight, vision, touch, smell and taste, and a very small number of ALS patients will also develop dementia. The term Huntington's disease (HD) generally refers to a genetic disorder that causes brain cells to die. As the disease progresses, the incoordination of body movements becomes more pronounced, and abilities gradually deteriorate until movement becomes difficult and speech is impossible. Mental abilities often decline into dementia. 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. The term "neuron" generally refers to a nerve cell, which is the main functional unit of the nervous system. A neuron can be composed of a cell body and its protrusions, an axon, and one or more dendrites. Neurons can transmit information to other neurons or cells by releasing neurotransmitters at synapses. The term "excitatory postsynaptic current (EPSC)" generally refers to the ion flow that causes an excitatory postsynaptic potential (EPSP). The EPSP is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of the postsynaptic membrane potential caused by the influx of positively charged ions into the postsynaptic cell is the key to opening the ligand Results of gating ion channels. The frequency and / or amplitude of the EPSC can be recorded using voltage clamp. The term "cognitive ability" generally refers to the ability of mental behavior to gain knowledge and understanding through thoughts, experiences and feelings. The concept of cognition may not be limited to psychological concepts / domains, and may include, for example, executive function, memory, perception, attention, emotion, motor control and / or interference processing. The term "Aβ" generally refers to any peptide resulting from the cleavage of β-amyloid precursor protein (APP) mediated by β-secretase. For example, the Aβ may include peptides of 37, 38, 39, 40, 41, 42, and 43 amino acids, and extend from the β-secretase cleavage site to amino acids 37, 38, 39, 40, 41, 42, or 43. The Aβ may also be an N-terminal truncated type of the above-mentioned peptides, such as pyroglutamic acid forms pE3-40, pE3-42, pE3-43, pE11-42, pE11-43, and the like. The term "Tau" generally refers to Tau proteins and components of a wide range of Tau aggregates (e.g., neurofibrillary tangles) associated with the stabilization of microtubules in neural cells. The Tau tangles may include oligomeric and / or fibrous forms of Tau, which are toxic. The Tau may also include all types and forms of Tau (e.g., different alternative splicing forms). 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...". The term "about" generally refers to a numerical range of 20% more or less than a particular value. For example, "about X" includes a numerical range of ±20%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2% or ±0.1% of X, where X is a numerical value. DETAILED DESCRIPTION OF THE INVENTION DIR and its functional fragments A form of intron retention (DIR) produced by abnormal splicing of human DDIT4L. Through sequence comparison, it was found that the nucleic acid sequence is conserved in primates, among which chimpanzees, which are closely related to humans, are highly conserved, while the conservation in macaques is relatively poor. However, it is not conserved in commonly used experimental animals such as rats, mice, dogs, and pigs. In the present application, the functional fragment 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., DIR) by at least one amino acid residue. In the present application, the functional fragment 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, and the comparison is 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 analysis is available through Publicly available from the National Center for Biotechnology Information (NCBI). In the present application, the expression level of DIR may include the expression level of the DIR gene, the transcription level of the DIR gene and / or the expression level of the DIR protein. For example, the expression level may include the amount of a polynucleotide, mRNA or amino acid product or protein of a specific gene (e.g., human DDIT4L gene; and / or, a gene (e.g., human DIR gene) encoding human DIR and / or its functional fragments (e.g., DIR-I, and / or, DIR-II)). The expression level may include the amount of a polynucleotide transcribed from a specific gene, a translated protein, or a fragment of a post-translationally modified protein. In the present application, QDLIR may be used in place of DIR, which may be a form of intron retention produced by abnormal shearing during expression of the human DDIT4L gene. In the present application, the gene encoding the DIR may be referred to as the DIR gene. In the present application, the expression level of the functional fragment of DIR (e.g., DIR-I, and / or, DIR-II) may include the expression level of the functional fragment gene encoding DIR, the transcription level of the functional fragment gene encoding DIR, and / or the expression level of the functional fragment protein of DIR. For example, the expression level may include the amount of polynucleotides, mRNA or amino acid products or proteins of a specific gene (e.g., a gene encoding a functional fragment of human DIR (e.g., DIR-I, and / or, DIR-II)). The expression level may include the amount of polynucleotides transcribed from a specific gene (e.g., a gene encoding a functional fragment of human DIR (e.g., DIR-I, and / or, DIR-II)), a translated protein, or a fragment of a post-translationally modified protein. In the present application, the DIR-I may be an amino acid sequence of IR (i.e., the amino acid sequence encoded by the retained intron, whose amino acid sequence is shown in SEQ ID NO: 3) consisting of the first 27 amino acids from the N-terminus. The amino acid sequence of DIR-I is shown in SEQ ID NO: 4. The DIR-II may be an amino acid sequence of IR consisting of the last 27 amino acids from the C-terminus. The amino acid sequence of DIR-II is shown in SEQ ID NO: 5. In the present application, the reduction can include that the expression level of the DIR is reduced by at least about 10% compared to the expression level of the original DIR in the subject. For example, it can be reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the expression level of DIR can be measured by utilizing substances selected from the following group: primers that specifically amplify the DIR gene, nucleic acid molecules that specifically bind to the DIR gene, nucleic acid molecules that specifically bind to the DIR protein, small molecules that specifically bind to the DIR protein, probes that specifically bind to the DIR protein, and polypeptides that specifically bind to the DIR protein. In the present application, the expression level of the functional fragment of DIR (e.g., DIR-I and / or DIR-II) can be measured by using a substance selected from the following group: a primer that specifically amplifies the functional fragment gene of DIR, a nucleic acid molecule that specifically binds to the functional fragment gene of DIR, a nucleic acid molecule that specifically binds to the functional fragment of DIR (e.g., DIR-I and / or DIR-II), Acid molecules, small molecules that specifically bind to functional fragments of DIR (e.g., DIR-I and / or, DIR-II), probes that specifically bind to functional fragments of DIR (e.g., DIR-I and / or, DIR-II), and polypeptides that specifically bind to functional fragments of DIR (e.g., DIR-I and / or, DIR-II). In the present application, the expression level of the DIR and / or its functional fragment can be measured by implementing a test selected from the group consisting of 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. For example, the expression level of the DIR described in the present application can be measured by qPCR, qRT-PCR, northern hybridization, western hybridization and / or ELISA detection. The expression level of the DIR can also be measured by directly performing analysis on a biological sample or on a protein / nucleic acid isolated from a sample. In the present application, the activity of the DIR and / or its functional fragment may include the biological activity of the DIR protein. For example, the biological activity may include affecting the excitability of neurons and / or inhibiting the activity of neurons. For example, the biological activity may include inhibiting cognitive ability by inhibiting the excitability of neurons and / or inhibiting the activity of neurons. In the present application, the biological activity may include being able to reduce the frequency of excitatory postsynaptic current (EPSC), and / or being able to reduce the amplitude of EPSC. For example, the reduction may include being able to reduce the frequency of excitatory postsynaptic current (EPSC) in the subject, and / or reducing the amplitude of EPSC, compared with the biological activity of the original DIR and / or its functional fragment in the subject, applying the DIR and / or its functional fragment and / or encoding the DIR and / or its functional fragment nucleic acid, and / or reducing the amplitude of EPSC in the subject. For example, the functional fragment DIR-I of the DIR can reduce the frequency of EPSC. For example, the reduction can include that the frequency of EPSC is reduced by at least about 10% after the DIR-I is applied compared with the frequency of the original EPSC in the subject. For example, it can be reduced 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. For example, the functional fragment DIR-II of the DIR can reduce the frequency of EPSC. For example, the reduction can include that the amplitude of EPSC is reduced by at least about 10% after the DIR-II is applied compared with the amplitude of the original EPSC in the subject. For example, it can be reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500%, or more. In the present application, the biological activity may include affecting cognitive ability. In the present application, the biological activity may include participating in a signaling pathway associated with Aβ deposition, and / or participating in a signaling pathway associated with Tau tangle generation. For example, The DIR and / or its functional fragment can inhibit cognitive ability. For example, the DIR and / or its functional fragment can inhibit cognitive ability by inhibiting the signaling pathway associated with Aβ deposition and / or inhibiting the signaling pathway associated with Tau tangle generation. In the present application, the reduction in the activity of the DIR and / or its functional fragment may include administering the DIR and / or its functional fragment and / or the nucleic acid encoding the DIR and / or its functional fragment, thereby reducing the cognitive ability of the subject, compared with the biological activity of the original DIR and / or its functional fragment in the subject. In the present application, the reduction can include that the biological activity of the DIR is reduced by at least about 10% compared to the biological activity of the original DIR in the subject. For example, it can be reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the expression level of the DIR and / or its functional fragment (e.g., the expression level in plasma) may be positively correlated with the Aβ level (e.g., the expression level in plasma). For example, the expression level of the DIR and / or its functional fragment may be positively correlated with the expression level of Aβ40. For example, the expression level of the DIR and / or its functional fragment may be positively correlated with the expression level of Aβ42. In the present application, the expression level of the DIR and / or its functional fragment (e.g., the expression level in plasma) can be positively correlated with the degree of reduction in the cognitive ability of the subject. For example, the expression level of the DIR and / or its functional fragment can increase with the progression of cognitive impairment (e.g., disease progression of MCI and / or AD). In the present application, the expression level of the DIR and / or its functional fragment (e.g., the expression level in plasma) can be positively correlated with the Aβ level (e.g., the Aβ-PET expression level in the cortex). In the present application, the expression level of the DIR and / or its functional fragment can be correlated with the formation of amyloid plaques in AD patients. In the present application, the expression level of the DIR and / or its functional fragment can be related to the storage of declarative memory. For example, the higher the expression level of the DIR and / or its functional fragment is, the lower the ability of the storage of declarative memory is. In the present application, the expression level of the DIR and / or its functional fragment can be related to the storage of associative learning. For example, the higher the expression level of the DIR and / or its functional fragment is, the lower the ability of the storage of associative learning is. In the present application, the reduction of the expression level of the DIR and / or its functional fragment can improve cognitive ability. In the present application, the reduction of the expression level can include that the expression level of the DIR is reduced by at least about 10% compared with the expression level of the original DIR in the subject. For example, it is possible to reduce 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 lower the expression level of the DIR and / or its functional fragment, the higher the cognitive ability (e.g., cognitive ability measured by novel object recognition behavior experiment). For example, when the reduction of the expression level is compared with the expression level of the original DIR in the subject, the expression level of the DIR is reduced by at least about 10%, and the cognitive ability can be improved by at least about 10%. For example, it can be improved by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the DIR or its functional fragment may be derived from mammals, for example, primates, or humans. In the present application, the DIR may comprise the amino acid sequence shown in SEQ ID NO:1. In the present application, the functional fragment of DIR may include the amino acid sequence encoded by the retained intron in DDIT4L. In the present application, the functional fragment of DIR may include the amino acid sequence shown in SEQ ID NO:3. In the present application, the functional fragment of DIR may comprise the amino acid sequence shown in any one of SEQ ID NOs: 4-5. In the present application, the DIR or its functional fragment can be involved in Aβ deposition. For example, the DIR or its functional fragment can induce Aβ deposition through gelsolin. Among them, the retained intron in DDIT4L (i.e., DIR-intron (IR), whose amino acid sequence is shown in SEQ ID NO: 3) can be the main region for DIR to interact with Aβ. Aβ can contribute to the interaction between DIR and gelsolin. In the present application, the DIR-intron can participate in Aβ deposition. In the present application, the DIR and / or its functional fragment can bind to gelsolin under pathological conditions, thereby causing Aβ deposition and amyloid plaque formation. DIR binder In one aspect, the present application provides a binding agent that binds to the intron retained splicing product DIR and / or its functional fragment of a DNA damage-inducible transcript 4-like transcript. In the present application, the binding of the binding agent to DIR 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 -1 or greater) of Ka (i.e., the equilibrium association constant for the binding interaction, which is 1 / M); or, -5 M (e.g., less than or equal to about 10 -5 M, less than or equal to about 10 -6 M, less than or equal to about 10 -7 M, less than or equal to about 10 -8 M, less than or equal to about 10 -9 M, less than or equal to about 10 - 10 M, less than or equal to about 10 -11 M, less than or equal to about 10 -12 M, less than or equal to about 10 -13The binding agent may bind or associate with DIR with an equilibrium dissociation constant Kd of 4 M or less. For example, the binding of the binding agent to DIR and / or its functional fragment may be in vivo or in vitro. In the present application, the binding agent may be isolated. 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. For example, the binding agent may include an ionotropic glutamate receptor (AMPARs) receptor subunit GluA1 and / or a fragment thereof. In the present application, the binding agent may include GluA1 and / or its fragments derived from various organisms. For example, the organism may include a mammal. For example, the organism may include a primate. For example, the organism may include a human. For example, the GluA1 and / or its functional fragments may include GluA1 and / or its functional fragments derived from humans. For example, the amino acid sequence of the GluA1 derived from humans may be the sequence shown in SEQ ID NO: 7. In the present application, the binding agent may include an amino terminal deletion, a carboxyl terminal deletion, and / or an internal deletion or substitution compared to the full length of GluA1, while the remaining amino acid sequence is generally the same as the corresponding position of the full length of GluA1. For example, the fragment of GluA1 may include a truncate of GluA1. For example, the fragment of GluA1 is at least 3, 4, 5, 6, 7, 8, 9, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 905 amino acids in length. For example, the fragment of GluA1 may include all fragments and functional variants thereof that can bind to DIR. For example, the fragment of GluA1 may include at least a portion of the amino acid sequence shown in positions 198 to 205 in human GluA1. For example, the binding agent may include the amino acid sequence shown at positions 198 to 205 of human GluA1. For example, the fragment of GluA1 may include a variant of the amino acid sequence shown at positions 198 to 205 of human GluA1. For example, the fragment of GluA1 may include a functional variant of the amino acid sequence shown at positions 198 to 205 of human GluA1. For example, the fragment of GluA1 may include a polypeptide having at least 60%, 70%, 80%, 90%, or 100% of the biological activity of the polypeptide having the amino acid sequence shown at positions 198 to 205 of human GluA1. For example, the fragment of GluA1 may include a polypeptide having at least 60%, 70%, 80%, 90%, or 100% of the DIR binding activity of the polypeptide having the amino acid sequence shown at positions 198 to 205 of human GluA1. For example, the fragment of GluA1 includes a protein or polypeptide in which one or more amino acids are substituted, deleted or added in the amino acid sequence shown in positions 198 to 205 of human GluA1. For example, the fragment of GluA1 may include a polypeptide having amino acid changes by substitution, deletion and / or insertion of at least 1, such as 1-30, 1-20 or 1-10, and for example 1, 2, 3, 4 or 5 amino acids in the amino acid sequence shown in positions 198 to 205 of human GluA1. For example, the binding agent may include a homolog of the amino acid sequence shown at positions 198 to 205 in human GluA1. For example, the binding agent may include a polypeptide having at least about 85% (e.g., at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence shown at positions 198 to 205 in human GluA1. In the present application, the binding agent can regulate the expression level and / or biological activity of DIR and / or its functional fragment. For example, the binding agent can reduce the expression level and / or biological activity of DIR and / or its functional fragment. For example, the binding agent can reduce the expression level and / or biological activity of the DIR and / or its functional fragment in the subject. In the present application, the binding agent can reduce the expression level of the DIR gene, the transcription level of the DIR gene and / or the expression level of the DIR protein. For example, the binding agent can reduce, for example, the human DDIT4L gene; and / or, the amount of polynucleotides, mRNA or amino acid products or proteins of genes (e.g., human DIR genes) encoding human DIR and / or its functional fragments (e.g., DIR-I, and / or, DIR-II). For example, the binding agent can reduce, for example, the human DDIT4L gene; and / or, the amount of polynucleotides, translated proteins or fragments of post-translationally modified proteins of genes (e.g., human DIR genes) encoding human DIR and / or its functional fragments (e.g., DIR-I, and / or, DIR-II). In the present application, the reduction can include that the expression level of the DIR is reduced by at least about 10% compared to the expression level of the original DIR in the subject. For example, it can be reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the reduction can include that the expression level of the functional fragment of the DIR is reduced by at least about 10% compared with the expression level of the original DIR in the subject. For example, it can be reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the binding agent can reduce the biological activity of the DIR and / or its functional fragment. In the present application, the reduction can include that the biology of the DIR or its functional fragment is reduced by at least about 10% compared with the biological activity of the original DIR in the subject. For example, it can be reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the binding agent can increase the frequency of excitatory postsynaptic current (EPSC), and / or increase the amplitude of EPSC. In the present application, the increase can include the frequency and / or amplitude of EPSC after administering DIR to the subject. Compared to the frequency and / or amplitude of EPSCs after administration of DIR and the binding agent, the frequency and / or amplitude of EPSCs is increased by at least about 1%. For example, it can be increased by at least about 2%, at least about 5%, 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 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 after the binding agent is administered to the subject, the cognitive ability of the subject is improved. For example, the improvement of the subject's cognitive ability can include that in a water maze behavior experiment, the subject's time in the quadrant where the platform is located is increased, the interval time to enter the quadrant where the platform is located is reduced, and / or the number of times the quadrant where the platform is crossed is increased. In the present application, the binding agent can inhibit the signaling pathway associated with Aβ deposition. In the present application, the binding agent can inhibit the signaling pathway associated with Tau tangle production. In the present application, the inhibition can include the expression level and / or biological activity of the molecules originally involved in the signaling pathway associated with Aβ deposition and / or the signaling pathway associated with Tau tangle production in the subject, and after the administration of the binding agent, the expression level and / or biological activity of these molecules is reduced by at least about 10%. For example, it can be reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more. In the present application, the binding agent can inhibit Aβ deposition and / or amyloid plaque formation through gelsolin. For example, the binding agent can inhibit Aβ deposition and / or amyloid plaque formation by inhibiting the binding of DIR / or its functional fragment to gelsolin. Isolated peptides In another aspect, the present application provides an isolated polypeptide comprising the amino acid sequence shown in SEQ ID NO: 8 (RLVVVDCE) and / or a functional variant thereof. In the present application, the isolated polypeptide can bind to DIR. For example, the binding of the isolated polypeptide to DIR can be specific. For example, the isolated polypeptide 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 - 1 or greater) of Ka (i.e., the equilibrium association constant for the binding interaction, which is 1 / M); or,- 5 M (e.g., less than or equal to about 10 -5 M, less than or equal to about 10 -6 M, less than or equal to about 10 -7 M, less than or equal to approximately 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 isolated polypeptide binds or associates with DIR with an equilibrium dissociation constant Kd of 1 M or less. For example, the binding of the isolated polypeptide to DIR and / or its functional fragment can be in vivo or in vitro. In the application, the isolated polypeptide can be used as a binding agent of DIR. For example, the isolated polypeptide can have one or more functions of a DIR binding agent. For example, the isolated polypeptide can regulate the expression level and / or biological activity of DIR and / or its functional variant. For example, the isolated polypeptide can reduce the expression level and / or biological activity of DIR and / or its functional variant. In the present application, the isolated polypeptide may include variants and / or homologs of the amino acid sequence shown in SEQ ID NO:8. For example, the isolated polypeptide may include a variant of the amino acid sequence shown in SEQ ID NO: 8. For example, the isolated polypeptide may include a functional variant of the amino acid sequence shown in SEQ ID NO: 8. For example, the isolated polypeptide may include 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: 8. For example, the isolated polypeptide may include a polypeptide having at least 60%, 70%, 80%, 90%, or 100% of the activity of binding to DIR of the polypeptide having the amino acid sequence shown in SEQ ID NO: 8. For example, the isolated polypeptide may include a protein or polypeptide having one or more amino acids substituted, deleted or added in the amino acid sequence shown in SEQ ID NO: 8. For example, the isolated polypeptide may include a polypeptide having at least 1, such as 1-30, 1-20 or 1-10, and for example 1, 2, 3, 4 or 5 amino acids substituted, deleted and / or inserted in the amino acid sequence shown in SEQ ID NO: 8 and having an amino acid change. For example, the isolated polypeptide may include a homolog of the amino acid sequence shown in SEQ ID NO: 8. For example, the isolated polypeptide may include a polypeptide having at least about 85% (e.g., at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence shown in SEQ ID NO: 8. In the present application, the isolated polypeptide can be a modified polypeptide. For example, the modification can include glycosylation, acetylation, phosphorylation, acylation, derivatization by known protective / blocking groups, proteolytic cleavage, and / or modification by non-naturally occurring amino acids. In the present application, the isolated polypeptide can form a multimer. For example, a homodimer can be formed. For example, a heterodimer can be formed with another protein or polypeptide. In the present application, the multimer can still have the ability to bind to DIR or its functional fragment. In the present application, the isolated polypeptide may form a fusion protein. In the present application, the isolated polypeptide may form an immunoconjugate. In the present application, the fusion protein and / or immunoconjugate may still have the ability to bind to DIR or its functional fragment. In the present application, the isolated polypeptide can be prepared by any method, including but not limited to, recombinantly produced polypeptides, synthetically produced polypeptides, extracted from cells or tissues and other sources. On the other hand, the present application also provides the use of the isolated polypeptide in the preparation of a medicament for preventing and / or treating a disease or condition, wherein the disease or condition includes cognitive impairment and / or neurodegenerative disease. On the other hand, the present application also provides a method for preventing and / or treating cognitive disorders and / or neurodegenerative diseases, which comprises the following steps: administering the isolated polypeptide to a subject in need thereof. On the other hand, the present application also provides the use of the isolated polypeptide in preventing and / or treating cognitive disorders. In the present application, the isolated polypeptide may be formulated to be suitable for oral administration and / or injection administration. On the other hand, the present application also provides the use of the isolated polypeptide in preparing a reagent for diagnosing and / or evaluating a disease, wherein the disease includes cognitive disorders and / or neurodegenerative diseases. On the other hand, the present application also provides a method for diagnosing and / or evaluating cognitive disorders and / or neurodegenerative diseases, which comprises using the isolated polypeptide. On the other hand, the present application also provides the use of the isolated polypeptide in diagnosing and / or evaluating neurodegenerative diseases. Immunoconjugates In another aspect, the present application provides an immunoconjugate, wherein the immunoconjugate comprises the binding agent described in the present application and / or the polypeptide described in the present application. For example, the immunoconjugate may include 1, 2 or more binding agents described herein and / or polypeptides described herein. The immunoconjugates described herein have biological activity. For example, biological activity may include the ability to bind DIR and / or its functional fragments in vivo or in vitro and cause a reaction. For example, the reaction includes but is not limited to reducing the expression level and / or biological activity of DIR and / or its functional fragments, increasing the frequency and / or amplitude of excitatory postsynaptic currents (EPSCs), improving cognitive ability, and inhibiting signaling pathways associated with Aβ deposition. Nucleic acid molecules, vectors, cells The present application provides one or more nucleic acid molecules, which can encode the conjugate described in the present application and / or the isolated polypeptide described in the present application. For example, each of the one or more nucleic acid molecules can encode a complete polypeptide variant or the fusion protein or immunoconjugate, or a portion thereof. The nucleic acid molecules described herein can be isolated. For example, they can be produced or synthesized by the following methods: (i) amplified in vitro, such as produced by polymerase chain reaction (PCR) amplification, (ii) produced by cloning and recombination, (iii) purified, such as by enzyme digestion 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 separation Subcloning 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 may be prepared from genomic DNA fragments, cDNA and RNA, all of which may 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. On the other hand, 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, a nucleic acid molecule described in the present application, and / or one or more vectors described in the present application. In certain embodiments, each or each host cell may contain one or more nucleic acid molecules or vectors described in the present application. In certain embodiments, each or each host cell may contain multiple (e.g., 2 or more) or multiple (e.g., 2 or more) nucleic acid molecules or vectors described in the present application. The vector described in the present application may be introduced into the cell by methods known in the art, such as electroporation, liposome transfection, etc. Pharmaceutical composition On the other hand, the present application provides a pharmaceutical composition, which may include the binding agent described herein, the polypeptide described herein, the 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 drug product suitable for pharmaceutical uses such as improving learning ability, treating cognitive disorders and / or treating neurodegenerative diseases such as Alzheimer's disease. For example, the pharmaceutical composition may be a composition comprising one or more active ingredients (such as the binding agent described herein) and one or more inert ingredients; and any combination, complex or aggregation of any two or more ingredients, or dissociation of one or more ingredients, or other types of reactions or interactions of one or more ingredients directly or indirectly obtained. Any product. 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 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 DIR in a sample. For example, the kit can detect the expression level and / or biological activity of DIR 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 DIR 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. Prevent and / or treat disease The present application provides the use of the binding agent described in the present application, the 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 and / or the pharmaceutical composition described in the present application 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 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. The present application provides the use of the binding agent described in the present application, the 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 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 reagents described herein can be administered in any manner. For example, the reagents described herein can be administered orally and / or by injection. For example, the reagents described herein can be formulated into a form suitable for its mode of use. For example, the reagents described herein can be formulated into a form suitable for oral administration and / or by injection. The binding agent described herein, the 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 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, drugs used as therapeutic agents can reduce the severity of a given disease state, but do not need to eliminate every manifestation of the disease to be considered a useful therapeutic agent. Similarly, the preventive administration of treatment constitutes a feasible preventive agent that does not need to completely and effectively prevent the onset of the disease. Simply reducing the effects of the disease in a 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 reducing the likelihood that the disease will occur or worsen, is sufficient. Detect DIR The present application provides a method for detecting DIR in a sample, which method comprises administering the binding agent described in the present application, the 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 kit described in the present application. The present application provides the use of the binding agent described in the present application, the 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 kit described in the present application in the preparation of a kit. For example, the kit can be used to detect DIR in a sample. In the present application, the binding agent described in the present application, the 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 described in the present application, The DIR in the sample can be detected by combining the material composition and / or the kit described in the present application with the DIR in the preparation of the kit. For example, the detection can include direct detection. For example, the detection can include indirect detection. For example, the detection of DIR in a sample as described herein may include detecting whether DIR exists in the sample. For example, the detection of DIR in a sample as described herein may include detecting the amount of DIR in the sample. For example, the DIR may include DIR and / or a nucleic acid encoding DIR. The detection of DIR 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 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-DIR complex. For example, the binding agent-DIR complex can be used for detection and analysis after releasing DIR, or the binding agent-DIR 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 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). Diagnose and / or evaluate disease The present application provides the use of the binding agent described herein, the polypeptide described herein, the immunoconjugate described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein, the pharmaceutical composition described herein and / or the kit described herein in the preparation of a reagent for diagnosing and / or evaluating a disease. The present application provides a method for diagnosing and / or assessing a disease, which comprises administering to a subject in need thereof the binding agent described herein, the 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 diagnosing and / or assessing a disease described herein. The present application provides the binding agent described in the present application, the polypeptide described in the present application, the immunoconjugate described in the present application, Use of the nucleic acid molecules, vectors, cells and / or pharmaceutical compositions described in the application in diagnosing and / or evaluating diseases. For example, the diagnosing and / or assessing a disease can include assessing a disease process. For example, wherein the disease can include a cognitive disorder. For example, wherein the disease can include a neurodegenerative disease. In the present application, the diagnosis and / or assessment of the disease may include detecting the content of DIR and / or nucleic acid encoding the DIR in a sample from a subject in need. For example, the present application diagnoses and / or assesses the disease, and may include comparing the content of the DIR and / or nucleic acid encoding the DIR in the sample of the subject with a normal control value, wherein the normal control value includes the content of the DIR and / or nucleic acid encoding the DIR in a normal subject. For example, the normal subject does not suffer from the cognitive disorder and / or the neurodegenerative disease. For example, when the content of the DIR and / or nucleic acid encoding the DIR in the sample of the subject is significantly higher than the normal control value, the subject is diagnosed as suffering from the cognitive disorder and / or the neurodegenerative disease. For example, the present application diagnoses and / or assesses the disease, and may include: comparing the content of the DIR and / or nucleic acid encoding the DIR in the sample of the subject with an early control value, wherein the early control value includes the content of the DIR and / or nucleic acid encoding the DIR measured by the same subject before. For example, the subject has been diagnosed with the cognitive disorder and / or the neurodegenerative disease. For example, when the content of DIR and / or nucleic acid encoding DIR in the sample of the subject is significantly higher than the early control value, the subject is diagnosed as having the cognitive disorder and / or aggravated disease progression of the neurodegenerative disease. For example, the diagnosis and / or assessment of the disease described in the present application may also include the following steps: detecting the content of markers associated with cognitive impairment and / or neurodegenerative diseases in the sample derived from the subject. For example, the markers associated with cognitive impairment and / or neurodegenerative diseases include AD7C-NTP, pTau-181, pTau-217 and / or Aβ1-42. For example, the diagnosis and / or assessment of a disease described herein may also include observing brain imaging of the subject. For example, the sample described in the present application may include a blood sample and / or a tissue or cell sample. For example, the sample described in the present application may include whole blood, serum, plasma and / or cerebrospinal fluid. 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 a patient with cognitive impairment and / or a patient with a neurodegenerative disease. 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 early cognitive impairment (MCI), mid-term cognitive impairment and late cognitive impairment. For example, the cognitive impairment may include cognitive impairment caused by normal aging, lewy 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 cognitive impairment may include amnestic MCI multi-cognitive domain impairment (aMCI-m). 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), mid-term 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 late cognitive impairment (e.g., memory loss, 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). In the present application, the subject may suffer from Alzheimer's disease. For example, the subject may be in the early stage of Alzheimer's disease, the middle stage of Alzheimer's disease and / or the late stage of Alzheimer's disease. In the present application, the disease may include cognitive impairment. In the present application, the cognitive impairment may include early cognitive impairment (MCI), mid-term cognitive impairment and late cognitive impairment. For example, the cognitive impairment may include cognitive impairment caused by normal aging, Lewis body dementia (LBD), frontotemporal lobe 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 cognitive impairment may include amnestic MCI multi-cognitive domain impairment (aMCI-m). In the present application, the disease may include a neurodegenerative disease. 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 diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal communication between cells and / or neurodegenerative diseases caused by impaired cell motility. Example Example 1 Identification of DIR By analyzing the transcripts of patients with Alzheimer's disease (AD), it was found that an alternative splicing form of the DDIT4L gene was highly expressed in patients. This splicing caused the retention of the second intron of DDIT4L, thereby producing a new transcript DIR. Specifically, the normal splicing body of the human DDIT4L gene will remove the intron part and connect the two adjacent exons during the formation of mRNA. In the abnormal splicing process, intron retention (IR) is caused, forming a new mRNA form of DIR (see Figure 1A, where NS represents the normal splicing body and IR represents the DIR formed by abnormal splicing). Identification of DDIT4L and DIR mRNA in normal subjects (NC) and patients with Alzheimer's disease (AD): Part of the brain tissue donated by normal subjects and patients with Alzheimer's disease was extracted and converted into cDNA, and then DDIT4L and DIR mRNA were identified by PCR. Primer design (forward primer: 5'-tgctggactgtggctatcac-3' (SEQ ID NO: 9); reverse primer 5'-acaaggacctttgagcaacca-3' (SEQ ID NO: 10)) In the two exons, due to abnormal splicing leading to intron retention, the PCR product of DIR (about 2000bp) is larger than the normally spliced ​​DDIT4L (about 200bp). The results of mRNA identification of DDIT4L and DIR are shown in Figure 1B. The open reading frame of DIR was cloned and exogenously expressed, and it was found that DIR could be normally translated into the corresponding DIR protein (whose amino acid sequence is shown in SEQ ID NO: 1) in vitro, and the protein could be secreted out of the cell. Specifically, the open reading frame of DIR (SEQ ID NO: 1) was constructed into the pCMV-flag vector, and the Flag-DIR plasmid and the control flag plasmid were transfected into HEK293 cells, respectively. After 48 hours, the cell culture medium and cell lysate were taken for Western Blot, and the expression of DIR was detected with a specific antibody, and actin was used as a control. The results are shown in Figure 1C. DIR in human blood was detected. Blood from 2 normal subjects and 7 AD patients of different ages (82, 55, 65, 53, 78, 68 and 58 years old, respectively) was taken for Western Blot, and its expression was detected with DIR-specific antibodies, and the Ponceau red-stained band was used as a loading control. The results are shown in Figure 1D. It can be seen that DIR can be specifically present in AD patients. Example 2 Biological functions of DIR 2.1 DIR interacts with gelsolin The plasmid expressing DIR was transfected into U87 cells. After 48 hours, the cells were lysed and the cell lysate was divided into two parts. Equal amounts of IgG and DIR antibody were added to each part for immunoprecipitation. The experimental products were separated by SDS-PAGE. Separate and soak the separated PAGE gel in Coomassie Brilliant Blue dye for 1 hour, then use decolorizing solution to wash away the dye that non-specifically adheres to the surface of the PAGE gel until the bands can be clearly seen in the PAGE gel. Then cut off the specific bands and perform mass spectrometry analysis to obtain the candidate molecule gelsolin. Then, the open reading frame of gelsolin (SEQ ID NO: 11) was cloned into the pEGFP-N3 vector to obtain the Gelsolin-GFP plasmid, and gelsolin-GFP and Flag or Flag-DIR plasmid were co-transfected into HEK293 cells. After 48 hours, the cells were lysed and the lysate was obtained and used for immunoprecipitation experiments with Flag antibodies. Finally, the binding of gelsolin and DIR was detected by GFP antibodies. 2.2 DIR inhibits the amplitude of excitatory postsynaptic current Brain slices were prepared from brain tissues of adult C57BL / 6 mice, and brain slices from the hippocampus were taken for electrophysiological recording. Changes in postsynaptic excitatory currents in brain slices were recorded before and after administration of IR peptides. The results are shown in Figure 2. The results show that after the application of the DIR, the current amplitude decreased, while the frequency of current discharge did not change. Example 3 Functional fragments of DIR and their biological functions DIR (i.e., QDLIR, whose amino acid sequence is shown in SEQ ID NO: 1) comprises an amino acid sequence encoded by the first exon (whose amino acid sequence is shown in SEQ ID NO: 2) and an amino acid sequence encoded by a retained intron (whose amino acid sequence is shown in SEQ ID NO: 3). The amino acid sequence (IR) encoded by the retained intron can be divided into two parts, namely IR-I (i.e., DIR-I, whose amino acid sequence is shown in SEQ ID NO: 4) consisting of the first 27 amino acids from the N-terminus and DIR-II (i.e., DIR-II, whose amino acid sequence is shown in SEQ ID NO: 5) consisting of the last 27 amino acids. See Figure 3 for details of the above structure. The function of the above IR fragments was verified by electrophysiological recording. First, the IR fragment was synthesized, brain slices of wild-type mice were incubated, and excitatory postsynaptic currents (EPSCs) were recorded (for specific methods, see Pavel et al., Curr Biol. Contemporary Biology, 26: 2194-2201

[2016] ). The results showed that IR can reduce the amplitude of EPSCs. Although no significant decrease in EPSC frequency was observed, a downward trend can be seen. The IR-I and DIR-II fragments were synthesized separately to screen the functional regions. The results showed that IR-I could reduce the frequency of EPSC but did not affect the amplitude of EPSC; although DIR-II had no significant effect on the amplitude and frequency of EPSC. However, it can be seen from the statistical results that DIR-II has a tendency to reduce the amplitude of EPSC and a tendency to increase the frequency of EPSC (see Figure 4). The above results show that IR has two functional areas. IR-I can reduce the frequency of EPSC, while DIR-II can To reduce EPSC amplitude. Example 4 DIR is involved in Aβ deposition 4.1 DIR induces Aβ deposition via gelsolin In AD patient samples, DIR was mainly co-localized with Aβ in the hippocampus (see Figure 5A). Interaction between DIR and Aβ was observed in transfected HEK293T cells, but DDIT4L (including DIR-exon) could not interact with Aβ (see Figure 5B, Figure 6A). These results indicate that DIR-intron (i.e., the amino acid sequence encoded by the retained intron, whose amino acid sequence is shown in SEQ ID NO: 3) may be the main region for DIR to interact with Aβ. Proximity ligation analysis (PLA) showed that DIR did not directly interact with Aβ (see Figure 5C). Using synthetic DIR-intron and Aβ proteins, it was found that DIR-intron could not directly bind to Aβ (see Figure 6B), indicating that DIR has another binding target. DIR was transfected into human brain cell lines, and the cell lysate was immunoprecipitated with rabbit DIR antibody (purchased from Jier Biochemical (Shanghai) Co., Ltd.). The results showed that a co-immunoprecipitated immunoreactive band with a molecular weight of about 85kDa was obtained (see Figure 5D). The bands were extracted and further analyzed by mass spectrometry. The analysis determined 12-15 peptides that matched human gelsolin (85kDa) and covered 35% of the gelsolin sequence (see Figure 5E). Gelsolin has been shown to interact with Aβ42 to form a complex that is transported into the circulation. Studies have shown that DIR interacts with gelsolin in DIR knock-in mice, HEK293T cells, and human tissues (see Figure 5F, G, Figure 6C). In HEK293T cell lysates transfected with DIR and endogenously expressed gelsolin, the addition of Aβ42 enhanced the interaction of DIR with gelsolin in a dose-dependent manner, indicating that Aβ contributes to the interaction between DIR and gelsolin (see Figure 5H). Moreover, when synthetic DIR-intron and Aβ42 proteins were added to purified gelsolin or HEK293T cell lysates, DIR-intron significantly enhanced the formation of insoluble Aβ42, which is the main component of amyloid plaques (see Figure 5I, Figure 6D). This suggests that the DIR-intron is involved in the deposition of Aβ. 4.2 DIR mediates the formation of Aβ amyloid plaques Thioflavine S is a specific marker for Aβ plaques in the brains of AD patients. However, thioflavine S failed to label amyloid plaques in the hippocampus of DIR knock-in mice (see Figure 7A) because mouse Aβ sequences could not be detected with thioflavine. However, amyloid plaques in hippocampal slices of DIR knock-in mice incubated with human Aβ40 peptide for 6 hours could be stained with Thioflavin S (see FIG7A ), and were consistent with the results of Thioflavin S staining of human Aβ plaques. Furthermore, triple immunostaining showed that in the hippocampus and cortex regions of AD patients, DIR colocalized with gelsolin and Aβ to a greater extent in dense core plaques than in diffuse plaques, whereas there was no obvious DIR or amyloid plaque staining in control subjects without AD (see Figure 7B, Figure 8). In dense-core plaques in the hippocampus and cortex of AD patients, Aβ signals were stronger than Thioflavin S and DIR, indicating that dense-core plaques were insoluble; in addition, soluble Aβ peptides were present in the peripheral regions (see Figure 7C). From the above results, it can be seen that the increase in DIR expression may lead to Aβ deposition and subsequent amyloid plaque formation under pathological conditions by binding to gelsolin. DIR may be an initiator of Aβ deposition and amyloid plaque formation (see Figure 11E). Example 5 DIR is associated with disease 5.1 Plasma DIR level as a diagnostic indicator The plasma levels of DIR were measured in 33 cognitively normal subjects (as a control group), 44 non-amnestic MCI (naMCI) patients, 42 amnestic MCI (aMCI) patients, and 31 patients clinically diagnosed with AD. Compared with the control group with normal cognition, the concentration of DIR in the plasma of naMCI, aMCI and AD patients gradually increased (see Figure 9A). In addition, the concentration of DIR in plasma was found to be positively correlated with the concentration of pTau181, but negatively correlated with the Aβ42 / 40 ratio, and negatively correlated with the severity of cognitive decline in the entire clinical range from normal cognition to naMCI, aMCI and AD. However, this trend was not observed for the concentration of total Tau (tTau) in plasma (see Figures 9B-9D). The plasma levels of DIR and pTau181 showed the potential to distinguish AD patients from cognitively normal individuals, with AUCs of AUC and AUC, respectively. DIR =0.86 and AUC pTau181 =0.86 (see Figures 9E and 9F); AUC in plasma Aβ42 / 40The ratio only reached 71% for distinguishing AD patients from normal controls (see Figure 9G). Plasma tTau levels could not effectively distinguish AD patients from controls (AUC = 0.55) (see Figure 10A). The comprehensive model combining DIR, pTau, and Aβ42 / 40 showed the potential to distinguish AD patients from cognitively normal controls, with an AUC of 96%, which was higher than the AUC (88%) obtained using pTau and Aβ42 / 40 (see Figure 9H). Compared with pTau181 (AUC = 0.63), Aβ42 / 40 (AUC = 0.59) and tTau (AUC = 0.56), DIR levels in plasma also showed better performance in distinguishing aMCI patients from cognitively normal patients (AUC = 0.73) (Figures 9I-9K, Figure 10B). The comprehensive model combining DIR, pTau, and Aβ42 / 40 showed better results in distinguishing aMCI individuals from cognitively normal controls, with an AUC of 81%, which is higher than the AUC obtained by pTau and Aβ42 / 40 (75%) (Figure 9L). 5.2 Correlation between plasma DIR levels and disease progression and plasma Aβ levels The researchers examined plasma from 12 MCI patients three years before when they were cognitively normal (as a baseline sample) and after they became ill. It was found that the plasma concentration of DIR in these MCI patient samples was higher than that in their baseline samples (Figure 11A). Furthermore, the plasma DIR levels of both MCI patients and cognitively normal subjects (as a control group) were positively correlated with the levels of Aβ40 and Aβ42 (see FIG. 11B , FIG. 12A ). These results suggest that an increase in DIR concentration in plasma occurs with the progression of cognitive impairment and is correlated with Aβ levels. 5.3 Correlation between plasma DIR levels and Aβ-PET levels The association between plasma DIR and Aβ-PET levels was detected. In AD / MCI patients, plasma DIR levels were significantly correlated with Aβ-PET levels throughout the cortex, and plasma DIR levels were closely correlated with Aβ-PET levels in the temporal lobe, indicating Aβ accumulation (see Figure 11C, Figure 12B). Aβ-positive individuals (n = 11) had higher DIR concentrations in plasma than Aβ-negative individuals (n = 26) (see Figure 11D). The DIR level in plasma has a good predictive value for Aβ-PET positivity (AUC = 0.90, see Figure 11D). These results show that the presence of DIR in plasma strongly reflects the formation of amyloid plaques in AD patients. Therefore, DIR is a potential biomarker for AD. Example 6 GluA1 is the binding target of DIR This example shows that GluA1 is the binding target of DIR. Figure 12A shows that the brain tissues of wild-type mice (C57BL / 6J) and DIR knock-in mice were used for co-immunoprecipitation experiments (co-IP experiments), followed by Coomassie Brilliant Blue staining, and the specific binding bands of DIR were found. Figure 12B shows that the specific binding bands of DIR were subjected to mass spectrometry analysis, and GluA1 was found to be a binding target of DIR. Example 7 GluA1 can bind to DIR This example demonstrates that GluA1 can bind to DIR. In vivo and in vitro experiments showed that GluA1 can bind to DIR. The binding of DIR and GluA1 was detected by co-immunoprecipitation, and the results are shown in Figure 13. Figure 13A shows that the brain tissues of wild-type mice and DIR knock-in mice were used for co-IP experiments, and the experimental results showed that DIR can bind to GluA1. Figure 13B shows that DIR and GluA1 were exogenously expressed in HEK293 cells and co-IP experiments were performed, and the results also showed that DIR can bind to GluA1. Example 8 The polypeptide fragment (R198-E205) derived from GluA1 can bind to DIR This example demonstrates that the polypeptide fragment (R198-E205) derived from GluA1 can bind to DIR. Figure 14A shows that GluA1 was found to bind to R198-E205 is the binding site for DIR, and GluA1 C204 Plays an important role in it. Figure 14B shows that adding a short peptide of GluA1 (R198-E205) at a final concentration of 10 uM to the cell lysate co-transfected with GluA1 and DIR can effectively block the binding between GluA1 and DIR, indicating that GluA1 R198-E205 It is the binding site of DIR. R198-E205 Can be developed into peptide drugs. FIG14C shows that after co-transfection of GluA1 or a point mutation of GluA1 (GluA1 C204A ) and DIR cell lysates were used for Co-IP experiments and found that GluA1 C204A The binding to DIR was weakened, indicating that the C204 site plays an important role in the binding of GluA1 and DIR. Example 9: Peptide fragments derived from GluA1 can reverse the inhibitory effect of DIR-induced sEPSC This example shows that the polypeptide fragment derived from GluA1 can reverse the inhibitory effect of sEPSC induced by DIR. As shown in Figure 15, the mouse brain tissue was placed in pre-cooled artificial cerebrospinal fluid (ACSF), and 95% O2 and 5% CO2 were continuously filled, and then cut into tissue slices about 350 microns thick using a Leica vibrating slicer. After selecting the appropriate brain slice, it was placed in an observation chamber filled with artificial cerebrospinal fluid. The observation chamber was fixed under the field of view of the microscope and fresh artificial cerebrospinal fluid was continuously perfused to maintain the activity of the brain tissue. Finally, electrodes were used to record the discharge of action potentials in the hippocampus. The results showed that after the administration of 5uM IR, the frequency and amplitude of the action potential discharge were reduced. At the same time, the administration of 5uM IR and 10uM GluA1 R198-E205 Later, the frequency and amplitude of action potential firing can be partially increased. Example 10 Administration of a polypeptide fragment derived from GluA1 can improve the learning ability of mice This example shows that administration of a polypeptide fragment derived from GluA1 can improve the learning ability of mice. As shown in Figure 16, the water maze experiment was performed on 3-month-old DIR homozygous mice. On the day of the experiment, the mice were acclimated to the experimental room 30 minutes in advance. The experiment was divided into training day and experimental day. The training day was 5-6 days, and the experimental day was 1 day. Before the experiment, the water tank was filled with 30 cm of water, the water temperature was maintained at 19-22 ° C, and talcum powder was added to the water to make it turbid. The water tank was divided into four directions: N, S, E and W. The platform was placed in the NE quadrant. The daily entry point of the mice was selected from a non-repeating combination of S, W, NW and SE. The room setting remained unchanged during the experiment, and specific patterns were posted around the water maze as distal cues. The room lighting was non-direct lighting. The entire experiment was recorded by camera video, and the video recording on the experimental day was analyzed using Etho Vision XT 14 software. On the training day: the platform was placed 0.5 cm below the water. The mouse entered the water from the designated entry point, facing the wall of the water tank, and the timer started for 1 minute at the same time. Stop timing when the mouse reaches the platform. If the mouse does not reach the platform within 1 minute, place the mouse on the platform or guide it onto the platform. After the mouse stays on the platform for 30 seconds, take it out, wipe it dry, and return it to the cage. There should be a 30-minute interval before the next entry into the water. Place the mouse at a new entry point and repeat the above experiment 3 times. The experimenter records the time it takes the mouse to get on the platform in each experiment. On the second day, repeat the above experiment. Train 4 times a day for a total of 5 to 6 days. Experimental day: Conduct the experiment 24 hours after the end of the training day. Remove the platform. The mouse enters the water from the SW quadrant, facing the wall of the water tank. Take the mouse out 1 minute later, wipe it dry, and return it to the cage. After the experiment, use Etho Vision XT 14 software to analyze the mouse behavior video and collect data The data included: escape latency to enter the target quadrant, number of platform crossings, and duration of stay in the target and non-target quadrants. The experimental operators and data analysts were double-blind. R198-E205 (1mg / kg, continuous intravenous administration for 7 days) can improve the learning ability of mice, including increasing the time in the quadrant where the platform is located, reducing the interval time to enter the quadrant where the platform is located, and increasing the number of times crossing the quadrant where the platform is located.

Claims

1. A binder that binds to the intron retained splicing product DIR of a DNA damage inducible transcript 4-like transcript and / or a functional fragment thereof.

2. The binding agent according to any one of claim 1, wherein the DIR and / or its functional fragment is derived from a mammal.

3. The binding agent according to any one of claims 1-2, wherein the DIR and / or its functional fragment is derived from a primate.

4. The binding agent according to any one of claims 1-3, wherein the DIR and / or its functional fragment are derived from humans.

5. The binding agent according to any one of claims 1 to 4, wherein the DIR comprises the amino acid sequence shown in SEQ ID NO:

1.

6. The binding agent according to any one of claims 1 to 5, wherein the functional fragment of DIR comprises an amino acid sequence encoded by a retained intron in DDIT4L.

7. The binding agent according to any one of claims 1-6, wherein the functional fragment of DIR comprises the amino acid sequence shown in any one of SEQ ID NOs: 4-5.

8. The binding agent of any one of claims 1-7, wherein the functional fragment of DIR retains at least part of the biological activity of DIR.

9. The binding agent according to claim 8, wherein the biological activity comprises the ability to reduce the frequency of excitatory postsynaptic current (EPSC) and / or the ability to reduce the amplitude of EPSC.

10. The binding agent according to any one of claims 9, wherein the reduction comprises administering the DIR and / or its functional fragment and / or a nucleic acid encoding the DIR and / or its functional fragment, thereby reducing the frequency of excitatory postsynaptic currents (EPSCs) in the subject and / or reducing the amplitude of EPSCs in the subject, compared to the biological activity of the original DIR and / or its functional fragment in the subject.

11. The binding agent according to claims 8-10, wherein the biological activity comprises affecting cognitive abilities.

12. The binding agent according to any one of claims 8 to 11, wherein the biological activity comprises participation in a signaling pathway associated with Aβ deposition, and / or participation in a signaling pathway associated with Tau tangle generation.

13. The binding agent according to any one of claims 8 to 12, wherein the biological activity comprises induction of Aβ deposition and / or amyloid plaque formation by gelsolin. 14 . The binding agent according to any one of claims 1 to 13 , wherein the DIR and / or a functional fragment thereof induces Aβ deposition and / or amyloid plaque formation by binding to gelsolin. 15 . The binding agent according to any one of claims 1 to 14 , wherein the expression level of the DIR and / or its functional fragment is positively correlated with the expression level of Aβ.

16. The binding agent according to claims 1-15, which is a protein and / or a polypeptide.

17. The binding agent according to any one of claims 1 to 16, comprising the receptor subunit GluA1 of ionotropic glutamate receptors (AMPARs) and / or a fragment thereof.

18. The binding agent according to claim 17, wherein the GluA1 and / or its fragment is derived from a mammal. 19 . The binding agent according to any one of claims 17 to 18 , wherein the GluA1 and / or a fragment thereof is derived from a primate. 20 . The binding agent according to any one of claims 17 to 19 , wherein the GluA1 and / or fragments thereof are derived from human.

21. The binding agent according to any one of claims 17 to 20, wherein the GluA1 comprises the amino acid sequence shown in SEQ ID NO: 7 and / or a variant thereof.

22. The binding agent according to any one of claims 1 to 21, comprising the amino acid sequence shown at positions 198 to 205 in GluA1 and / or a functional variant thereof.

23. The binding agent according to any one of claims 1 to 22, comprising the amino acid sequence shown in SEQ ID NO: 8 and / or a functional variant thereof.

24. The binding agent according to any one of claims 1-23, which is capable of regulating the expression level and / or biological activity of the intron-retained splicing product DIR of the DNA damage-inducible transcript 4-like transcript and / or its functional fragments.

25. The binding agent according to claim 24, wherein the expression level comprises the expression level of the gene encoding the DIR / or its functional fragment, the transcription level of the gene encoding the DIR / or its functional fragment and / or the expression level of the DIR / or its functional fragment.

26. The binding agent according to any one of claims 1-25, which is capable of reducing the expression level and / or biological activity of the DIR and / or its functional fragment in a subject.

27. The binding agent according to claim 26, wherein the reduction comprises a reduction of at least about 10% in the expression level and / or biological activity of the DIR and / or its functional fragment compared to the original expression level and / or biological activity of the DIR and / or its functional fragment in the subject.

28. An isolated polypeptide comprising the amino acid sequence shown in SEQ ID NO: 8 and / or a variant thereof.

29. An immunoconjugate comprising the binding agent of any one of claims 1-27 and / or the polypeptide of claim 28.

30. A nucleic acid molecule encoding the binding agent of any one of claims 1-27 and / or the polypeptide of claim 28.

31. A vector comprising the nucleic acid molecule of claim 30.

32. A cell comprising the binding agent of any one of claims 1-27, the polypeptide of claim 28, the nucleic acid molecule of claim 30 and / or the vector of claim 31.

33. A pharmaceutical composition comprising the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31 and / or the cell of claim 32, and optionally a pharmaceutically acceptable carrier.

34. A kit comprising the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32 and / or the pharmaceutical composition of claim 33.

35. The kit according to claim 34, which is used for detecting DIR in a sample.

36. A method for detecting DIR in a sample, the method comprising administering the binding agent of any one of claims 1-27, the polypeptide molecule of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32, the pharmaceutical composition of claim 33 and / or the kit of any one of claims 34-35.

37. Use of the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32 and / or the pharmaceutical composition of claim 33 in the preparation of a kit.

38. Use of the binding agent of any one of claims 1 to 27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32 and / or the pharmaceutical composition of claim 33 in the preparation of an agent for preventing and / or treating a disease, wherein the disease comprises cognitive impairment.

39. Use of the binding agent of any one of claims 1 to 27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32 and / or the pharmaceutical composition of claim 33 in the preparation of an agent for preventing and / or treating a disease, wherein the disease comprises a neurodegenerative disease.

40. Use of the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32, the pharmaceutical composition of claim 33 and / or the kit of any one of claims 34-35 in the preparation of an agent for diagnosing and / or assessing a disease, wherein the disease comprises cognitive impairment.

41. Use of the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32, the pharmaceutical composition of claim 33 and / or the kit of any one of claims 34-35 in the preparation of an agent for diagnosing and / or assessing a disease, wherein the disease comprises a neurodegenerative disease.

42. The use according to any one of claims 37-41, wherein the cognitive impairment comprises cognitive impairment caused by normal aging, Lewis body dementia (LBD), frontotemporal dementia and / or vascular dementia.

43. The use according to any one of claims 37-42, wherein the inducing disease of cognitive impairment comprises Alzheimer's disease, multi-infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD).

44. The use according to any one of claims 37-43, wherein the cognitive impairment comprises early cognitive impairment (MCI), mid-stage cognitive impairment and late stage cognitive impairment.

45. The use according to any one of claims 37-44, wherein the cognitive impairment comprises amnestic MCI with impairment of multiple cognitive domains (aMCI-m).

46. ​​The use according to any one of claims 37-45, wherein the neurodegenerative disease comprises an acute neurodegenerative disease and a chronic neurodegenerative disease.

47. The method of any one of claims 37-46, 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.

48. The use according to any one of claims 37-47, wherein the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

49. The use according to any one of claims 37-48, wherein the neurodegenerative disease comprises Alzheimer's disease.

50. The use according to any one of claims 37-49, wherein the neurodegenerative disease comprises early Alzheimer's disease, middle Alzheimer's disease and / or late Alzheimer's disease.

51. The use according to any one of claims 37-50, wherein the subject comprises a mammal.

52. The use according to any one of claims 37-51, wherein the subject comprises a human.

53. The use according to any one of claims 37-52, wherein the subject comprises a patient with a neurodegenerative disease and / or a patient with a cognitive disorder.

54. The use according to any one of claims 37-53, wherein the subject comprises an Alzheimer's disease patient.

55. The use according to any one of claims 37-54, wherein the subject is in the elderly stage.

56. The use according to any one of claims 37-55, wherein the agent is formulated for oral administration and / or injection administration.

57. A method for preventing and / or treating cognitive disorders, comprising administering to a subject in need thereof the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32 and / or the pharmaceutical composition of claim 33.

58. A method for preventing and / or treating a neurodegenerative disease, comprising administering to a subject in need thereof the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32 and / or the pharmaceutical composition of claim 33.

59. A method for diagnosing and / or assessing cognitive impairment, comprising using the binding agent described in any one of claims 1-27, the polypeptide described in claim 28, the immunoconjugate described in claim 29, the nucleic acid molecule described in claim 30, the vector described in claim 31, the pharmaceutical composition described in claim 32 and / or the kit described in claim 33.

60. A method for diagnosing a neurodegenerative disease, and / or assessing a neurodegenerative disease, comprising using the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the pharmaceutical composition of claim 32 and / or the kit of claim 33.

61. Use of the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32 and / or the pharmaceutical composition of claim 33 in preventing and / or treating cognitive disorders.

62. Use of the binding agent of any one of claims 1 to 27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the cell of claim 32 and / or the pharmaceutical composition of claim 33 in preventing and / or treating neurodegenerative diseases.

63. Use of the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the pharmaceutical composition of claim 32 and / or the kit of claim 33 in diagnosing and / or assessing cognitive disorders.

64. Use of the binding agent of any one of claims 1-27, the polypeptide of claim 28, the immunoconjugate of claim 29, the nucleic acid molecule of claim 30, the vector of claim 31, the pharmaceutical composition of claim 32 and / or the kit of claim 33 in diagnosing and / or evaluating a neurodegenerative disease.

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