Application of cathepsin S in cognitive impairment or neurodegenerative disease caused by aging

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of cathepsin S in cognitive impairment or neurodegenerative diseases caused by aging. The invention discloses application of cathepsin S in diagnosis or treatment of cognitive impairment or neurodegenerative diseases. Researches find that the expression level of cathepsin S in an aged mouse model is increased, and the spatial learning and memory levels of aged mice are changed by adjusting or inhibiting the expression level of cathepsin S. Changes in the behavior and cognitive function of neurodegenerative diseases are predicted through the expression level of cathepsin S, and it is possible to improve the cognitive function level of neurodegenerative diseases by adjusting or inhibiting the expression or activity of cathepsin S.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to the application of cathepsin S in cognitive dysfunction or neurodegenerative diseases caused by aging. Background Art

[0002] With the acceleration of population aging, the United Nations predicts that by 2050, one-sixth of the world's population will be over 65 years old, and more and more people are facing aging. The process of aging is a complex process of the body, which is the result of the interaction of genetic factors, epigenetic factors, inflammatory factors, etc. It is manifested as the decline of the body's physiological functions and is the main risk factor for human chronic diseases. Like other systems, the nervous system is also affected by aging. During the aging process of the human body, the brain is one of the first organs to age. The aging of the nervous system will damage behavior and cognitive functions and easily lead to neurodegenerative diseases. Common neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), frontotemporal dementia, and amyotrophic lateral sclerosis (ALS). These neurodegenerative diseases have neither an efficient treatment method nor an effective protection method, which will bring a huge economic burden to families and society and also pose a huge challenge to the medical system.

[0003] As a member of the cysteine protease family, cathepsin S (CTSS) plays an important role in the endocytic pathway and is responsible for protein degradation. Different from other cysteine proteases that rely on an acidic environment for activation, cathepsin S can be activated in both neutral and acidic environments. Previous studies have shown that CTSS mainly mediates the processing and presentation of major histocompatibility complex II (MHC-II) antigens, indicating its involvement in the pathogenesis of immune-related diseases. In the nervous system, CTSS is mainly expressed in microglial populations. Although its main role is to process microglial MHC-II and enhance the ability of microglia to capture antigen fragments, more and more evidence shows that CTSS plays a key regulatory role in the neurotoxic reactions caused by neurological diseases. Some studies have shown that an increase in the activity of CTSS has been observed in neurodegenerative diseases such as AD and ALS. However, the role of CTSS in aging and neurodegenerative diseases, especially in the cognitive decline caused by them, has not been answered.

[0004] The invention patent CN201280029920.5 discloses a cathepsin inhibitor for treating neuron loss mediated by microglia in the central nervous system, mainly a method for treating CNS disorders, diseases and injuries, especially neurodegenerative diseases, using a cathepsin S inhibitor and a compound of formula I as a cathepsin S inhibitor. The invention mainly includes a pharmaceutical composition containing a compound for treating CNS disorders, but does not emphasize the role of CTSS in the diagnosis of aging and neurodegenerative diseases and its regulatory role in cognitive behavior, which is significantly different from this solution. Summary of the Invention

[0005] The purpose of the present invention is to provide the application of cathepsin S in cognitive dysfunction or neurodegenerative diseases caused by aging, predict behavior and cognitive function by detecting the expression level of cathepsin S, and prevent and improve the cognitive function level of neurodegenerative diseases by intervening in CTSS expression or inhibiting its activity.

[0006] The technical solution of an application of cathepsin S in cognitive dysfunction or neurodegenerative diseases caused by aging of the present invention is as follows: The application of cathepsin S in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases.

[0007] Preferably, the cathepsin S is used as a marker for detecting cognitive dysfunction or neurodegenerative diseases.

[0008] Preferably, it is characterized in that the cathepsin S is used for preparing a diagnostic reagent or kit for detecting cognitive dysfunction or neurodegenerative diseases.

[0009] More preferably, the diagnostic reagent or kit contains a detection reagent for detecting cathepsin S.

[0010] Even more preferably, the activity and expression level of the cathepsin S are negatively correlated with neurodegenerative diseases and cognitive dysfunction.

[0011] Preferably, the application of the cathepsin S as an intervention target in screening or preparing drugs for treating cognitive dysfunction or neurodegenerative diseases.

[0012] More preferably, the overexpression of the cathepsin S is negatively correlated with spatial learning and memory behavior.

[0013] Even more preferably, the cognitive dysfunction is caused by neurodegenerative diseases.

[0014] Still more preferably, the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and amyotrophic lateral sclerosis.

[0015] Preferably, the expression level of cathepsin S is positively correlated with age and senescence.

[0016] Beneficial effects: Through research, the present invention finds that the expression level of cathepsin S increases in the senescence mouse model. By adjusting or inhibiting the expression level of cathepsin S, the spatial learning and memory levels of senescent mice are both changed. The changes in the behavior and cognitive function of neurodegenerative diseases can be predicted through the expression level of cathepsin S, and it is possible to improve the cognitive function level of neurodegenerative diseases by adjusting or inhibiting the expression or activity of cathepsin S. Description of the Drawings

[0017] Figure 1 are the genome-wide transcriptome expression levels of the hippocampal tissues of young and senescent mice. Among them, A is the principal component analysis diagram of RNA sequencing (RNA-seq) of the hippocampal tissues of young and senescent mice; B is the volcano plot of differential gene expression between young and senescent mice; C is the heat map of differential gene expression between young and senescent mice; D is the gene ontology (GO) enrichment analysis diagram of differential genes between young and senescent mice; Figure E is the gene set enrichment analysis (GSEA) diagram of differential genes between young and senescent mice.

[0018] Figure 2 Among them, A is the content of CTSS in the sera of young healthy subjects (youth group) and old healthy subjects (elderly group); B is the co-staining immunofluorescence intensity of CTSS and NeuN in young and senescent mice; C and D are the CTSS protein expression levels in young and senescent mice; E is the co-staining immunofluorescence intensity of CTSS and 6E10 in young and senescent mice; F is the plaque number level in young and senescent mice; G is the plaque area level in young and senescent mice.

[0019] Figure 3 are the spatial learning and memory levels after overexpressing CTSS in the hippocampal region of young mice. Among them, A is the schematic diagram of the overexpressed CTSS structure; B is the immunofluorescence map of the sub-regions of the hippocampal CA1, CA3, and DG in young mice after overexpressing CTSS; C is the CTSS mRNA expression level in the mice overexpressing CTSS and the control young mice; D, E, F, G, and H are the spatial learning and memory levels of the mice overexpressing CTSS and the control young mice.

[0020] Figure 4To investigate the spatial learning and memory levels of aged mice after knocking down CTSS in the hippocampal region. Among them, A is the schematic diagram of knocking down CTSS; B is the immunofluorescence images of the hippocampal CA1, CA3, and DG subregions of mice after knocking down CTSS; C is the CTSS mRNA expression levels of mice with knocked-down CTSS and control mice; D, E, F, G, and H are the spatial learning and memory levels of mice with knocked-down CTSS and control mice.

[0021] Figure 5 For the immunofluorescence intensity and spatial learning and memory levels of APP / PS1 transgenic mice treated with the CTSS inhibitor LY300328. Among them, A is the schematic diagram of the experimental time arrangement; B is the cannula implantation in the hippocampal region; C and D are the Iba1 fluorescence intensity levels of control mice and LY300328-treated mice; E and F are the 6E10 fluorescence intensity levels of control mice and LY300328-treated mice; G, H, I, J, and K are the spatial learning and memory levels of control mice and LY300328-treated mice. Specific implementation manners

[0022] The embodiments of the present invention will be described in detail below. The examples of the embodiments are shown in the accompanying drawings. The embodiments described below by referring to the drawings are exemplary and are intended to explain the present invention, and should not be construed as a limitation to the present invention.

[0023] I. Experimental methods In order to explore the role of cathepsin S (CTSS) in neurodegenerative diseases, especially in neurodegenerative diseases, the present invention adopts the following technical solutions: 1. Animal information Young mice: 2-month-old male C57BL / 6J mice, with a body weight of about 25 grams, a total of 28 mice; Aged mice: 12-month-old male C57BL / 6J mice, with a body weight of about 30 grams, a total of 37 mice; APP / PS1 transgenic mice: 8-month-old male B6-Tg(PrP-hAPP / hPS1) mice, with a body weight of about 28 grams, a total of 16 mice.

[0024] 2. Molecular biology reagents CTSS inhibitor LY3000328 (MCE Company); Plasmid PcDNA 3.1-CTSS (General Biology Co., Ltd.); Plasmid CTSS-EGFP-N1 (General Biology Co., Ltd.); Plasmid pLKO.1-sh-CTSS-puro (General Biology Co., Ltd.); Plasmid pLKO.1-sh-CTSS-EGFP-puro (General Biosystems Co., Ltd.); Ploki-pAAV-hSyn-CTSS-3xFlag-P2A-EGFP-WPRE (titer: 1×10 12 gc / μL) (OBIO Technology); pAAV-hSyn-3xFlag-P2A-EGFP-WPRE (titer: 1×10 12 gc / μl) (OBIO Technology); pAAV-hSyn-EGFP-3xFlag-shRNA-WPRE (titer: 1×10 12 gc / μl) (OBIO Technology).

[0025] 3. Immunofluorescence and Imaging Mouse brains were cut into 30-μm thick brain slices using a cryostat (CM3050S, Leica). The brain slices were stored in a protective solution containing 30% sucrose, 1% polyvinylpyrrolidone, 5 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, and 30% ethylene glycol dissolved in deionized water at -20°C for future use.

[0026] Before use, the brain slices were washed three times with 1× phosphate-buffered saline (PBS) (0.01 M), and then blocked with 0.3% immunostaining permeabilization solution (Triton-X-100) and 5% goat serum for 1.5 h at room temperature. The brain slices were then incubated with primary antibodies, including CTSS (Santa Cruz, sc-74429), mature neuron marker (NeuN) (Millipore, #Mab377), microglia marker (Iba1) (Abcam, 178846), and Aβ marker 6E10 (Biolegend, #803014), overnight at 4°C. The primary antibodies were aspirated, and the slices were washed three times with 1× PBS, followed by incubation with Alexa 488-, 546-, or 633-conjugated secondary antibodies (Invitrogen), and then stained with 4',6-diamidino-2-phenylindole (DAPI) (CST, #4083) for the nuclei.

[0027] The stained brain sections were placed on glass slides and then imaged using a (Zeiss 980) laser confocal microscope. For the co-localization imaging of CTSS and NeuN, a 60x / 1.4 objective lens was used. For the co-localization imaging of CTSS and 6E10, 20× / 0.8 objective lens (Zeiss) and 60× / 1.41 objective lens (Zeiss) were used. A 20× / 0.95 objective lens (Zeiss) was used to detect the number of Iba1-positive cells. A 10× / 0.45 objective lens (Zeiss) was used to detect the plaques of 6E10.

[0028] 4. ELISA The concentration of CTSS in patient sera was evaluated using a human CTSS ELISA kit (Elabscience, #E-EL-H5431c). All human serum samples were obtained from the clinical laboratory of a affiliated hospital in Zhengzhou and approved by the corresponding ethics committee. On November 11, 2023, a total of 40 male healthy volunteers participated in the study of this application. The volunteers were divided into a young group (n = 20, average age 31.80 ± 3.12 years) and an elderly group (n = 20, average age 66.90 ± 2.86 years). Exclusion criteria applied to the participants: (1) patients who were taking medications or receiving hospital treatments; (2) patients with neurological diseases such as cognitive dysfunction because they were unable to communicate.

[0029] 5. Western Blot Protein extraction: Proteins were extracted from the hippocampal tissues of mouse brains using RIPA lysis buffer (Beyotime, #P0013B) supplemented with protease inhibitor (100 mM) (Beyotime, #ST506) and phosphatase inhibitor (50X) (Beyotime #P1081).

[0030] The protein concentration was detected using a BCA protein assay kit (Beyotime, #P0012). Then, the corresponding volume of 5X loading buffer was added, mixed well, heated at 95°C for 5 min, and used for subsequent experiments or stored at -20°C.

[0031] Electrophoresis: A 12% polyacrylamide gel (SDS-PAGE gel) was used. The gel plate was placed in the electrophoresis tank, and 1X electrophoresis buffer was added. The comb on the gel plate was pulled out vertically upward to expose the pores on the gel. According to the protein loading amount of 30 μg per well, the corresponding volume was added. Markers were added to both ends of the gel to mark the positions. Electrophoresis was carried out at a constant voltage of 140 V until the bromophenol blue ran to the bottom of the gel and then stopped.

[0032] Transfer membrane: Open the gel plate, cut off the comb teeth on the gel and the redundant gel on the left and right, then cut a nitrocellulose membrane corresponding to the size of the gel, and place it in the transfer membrane clamp in the order of sponge - filter paper - gel - nitrocellulose membrane - gel - filter paper - sponge, paying attention to "black gel and white membrane", and there should be no air bubbles between the gel and the membrane. Then put it into the transfer membrane tank, add the transfer membrane solution, and place the transfer membrane tank in a foam box filled with ice to prevent damage to the membrane due to excessive heat during the transfer membrane process. Use a constant current of 300 mA to transfer the membrane for 1.5 h.

[0033] Blocking: After the transfer membrane is completed, place the membrane in 5% bovine serum albumin (BSA) for blocking for 1 h, and then wash it with 1X Tris-buffered saline with Tween (TBST) for 10 min.

[0034] Primary antibody incubation: According to the molecular weight of the protein to be detected, cut the membrane according to the position indicated by the Marker, add the corresponding primary antibody respectively, and incubate overnight on a shaker at 4°C.

[0035] Secondary antibody incubation and chemiluminescence: Recover the primary antibody the next day, wash the membrane 3 times with an appropriate amount of 1X TBST on a shaker, 10 min each time, prepare the corresponding secondary antibody and incubate at room temperature for 1 h. Then wash the membrane 3 times with 1X TBST, 10 min each time. Use the luminescent solution to expose and image on a LI-COR Odyssey imager. After saving the picture, perform analysis, and the expression of the protein is represented by relative optical density.

[0036] 6. Stereotaxic injection Use 1% sodium pentobarbital, and inject intraperitoneally according to the weight of the mouse at a dose of 50 mg / kg to deeply anesthetize the mouse. Remove the hair on the mouse's head completely, place it on the stereotaxic device for fixation, dip a cotton swab in 75% ethanol and disinfect the skin surface 3 times, cut the surface skin to expose the skull, use the stereotaxic device to adjust the top surface of the skull to the same horizontal position, and then at 2 mm behind the bregma point, 1.5 mm to the left and right of the midline respectively, carefully drill through the skull with a skull drill, taking care not to damage the cerebral cortex. Use a glass electrode to suck the virus and inject it into the mouse hippocampal region at a depth of 2.0 mm at a speed of 3 nl / s. After the injection is completed, keep the glass electrode needle in place for 5 min to prevent the virus body fluid from overflowing. After the mouse is injected with the virus, let the mouse recover for 2 weeks, and then perform the behavioral experiment.

[0037] 7. Morris water maze experiment For the Morris water maze experiment in mice, a pool with a diameter of 120 cm was used, and an escape platform with a diameter of 10 cm was selected. Water was filled to a level 1 cm above the escape platform, and an appropriate amount of titanium dioxide powder was used to make the water sufficiently turbid. The water temperature was adjusted to 19 - 22 °C. The water maze was divided into 4 quadrants, and patterns of different colors and shapes were placed on the pool in each quadrant to help the mice memorize. For the water maze experiment, a quiet environment was chosen, and cloth curtains were set around the pool to prevent the mice from being affected by the outside world.

[0038] One day before the experiment, the platform was not placed, and the mice were allowed to swim adaptively for 90 s. During the experiment, the mice were put into the water from one quadrant and allowed to swim. If the platform was found within 60 s, the time to find the platform was recorded. If the platform was not found within 60 s, the mice were manually placed on the platform for 10 s to help them remember. The mice were trained 4 times a day, and the 4 times were in different quadrants. The experimental results were the average of the 4 times. The mice were continuously trained for 5 days. On the 5th day, the platform was removed, and the memory exploration ability of the mice was tested using the camera device on the top of the water maze.

[0039] 8. Cannula implantation Sixteen 8 - month - old male APP / PS1 mice were selected. According to the body weight of the mice, 1% sodium pentobarbital was intraperitoneally injected at a dose of 50 mg / kg to deeply anesthetize the mice. The hair on the heads of the mice was completely removed, and they were fixed on a stereotaxic device. After disinfection, the surface skin was incised to expose the skull. Using the stereotaxic device, the top surface of the skull was adjusted to the same horizontal position. Then, a cannula was implanted at a position 2 mm posterior to the bregma, 1.5 mm lateral to the midline, and with a depth of 2 mm. The mice were implanted with the cannula for more than 10 days. After the water maze experiment training, CTSS inhibitor (1 μl in total) was continuously injected through the cannula at a rate of 0.2 μL / min for 5 days, or an equal amount of the control reagent dimethyl sulfoxide (DMSO).

[0040] II. Results and analysis RNA - seq was performed on the hippocampi of 3 young mice and 3 senescent mice respectively. The preparation of RNA - seq libraries and deep sequencing were carried out using the Illumina NovaSeq6000 sequencing platform (Linkage Biotechnology (Kunming) Co., Ltd.). The PE150 sequencing method was used. FastQC was used to evaluate the read quality. The reads were aligned to the mouse genome (mm10) using hisat2 with default parameters, and the reads were corrected using Featurecount. To evaluate the changes in the whole - genome transcriptomics, genes with |log2FoldChange| > 1 and P - value < 0.05 were used as the screening criteria. The DESeq2 package in R language was used to identify the differentially expressed genes in the brains of young mice and senescent mice. GO enrichment analysis and GSEA enrichment analysis were performed on the differentially expressed genes. The results are as Figure 1 shown, asFigure 1 As shown in A, there are obvious differences in the principal component analysis of RNA-seq in the hippocampal tissues of young and aged mice; Figure 1 As shown in B and 1C, the CTSS gene is significantly upregulated in aged mice; Figure 1 As shown in D and 1E, the differential genes between aged and young mice are significantly enriched in the antigen processing and presentation pathway. In summary, Figure 1 the results show that the expression level of the CTSS gene in the hippocampus of aged mice is significantly increased compared with that of young mice.

[0041] From Figure 2 A, it can be seen that the concentration of CTSS in the serum of old healthy subjects (elderly group) is significantly higher than that of young healthy subjects (young group); immunofluorescence was performed on young and aged mice. Figure 2 B is the co-staining immunofluorescence image of CTSS and NeuN in young and aged mice. As shown in Figure 2 B, the fluorescence intensity of CTSS co-localized with NeuN in aged mice is significantly higher than that in young mice. Figure 2 C and 2D are the expression levels of CTSS protein in the hippocampal brain regions of young and aged mice. The results show that the expression level of CTSS protein in the hippocampal brain region of aged mice is significantly higher than that of young mice. Figure 2 E is the co-staining immunofluorescence image of CTSS and 6E10 in young and aged mice. As shown in Figure 2 E, the fluorescence intensity of CTSS in the hippocampal region of aged mice is significantly higher than that of young mice, and the CTSS intensity is significantly increased in the area adjacent to Aβ plaques. Figure 2 F and 2G are the levels of plaque number and plaque area in young and aged mice. The results show that the plaque number and area in aged mice are significantly higher than those in young mice. As shown in Figure 2 it can be seen that the expression level of CTSS is positively correlated with age and aging-related phenotypes.

[0042] In young mice with overexpression of CTSS in the hippocampus, the spatial memory behavior of the mice was observed. The behavioral experiment used the water maze experiment. Figure 3 A is the schematic diagram of the overexpression of CTSS; as shown in Figure 3 B, after overexpression of CTSS in the hippocampus of young mice, the CTSS immunofluorescence in the CA1, CA3, and DG sub-brain regions was enhanced; as shown in Figure 3 C, the CTSS mRNA expression level in the mice overexpressing CTSS is significantly higher than that in the control virus mice; as shown in Figure 3 D, the escape ability of the mice overexpressing CTSS is decreased compared with that of the control mice; as shown in Figure 3 E, the exploration ability of the mice overexpressing CTSS is decreased after evacuating from the escape platform; as shown in Figure 3 F, the residence time of the mice overexpressing CTSS in the target quadrant is reduced;Figure 3 As shown in G, the latency to find the platform position was longer in the mice with overexpressed CTSS; Figure 3 as shown in H, the number of times of crossing the escape platform was fewer. Figure 3 It can be seen that overexpression of CTSS in the hippocampus of young mice impairs spatial learning and memory behaviors.

[0043] Subsequently, CTSS was knocked down in aging mice, and the spatial memory behaviors of the mice were observed. Figure 4 A is the schematic diagram of knocking down CTSS; Figure 4 as shown in B, after knocking down CTSS in the hippocampus of aging mice, the immunofluorescence intensity of CTSS in the CA1, CA3, and DG sub-regions of the brain decreased; Figure 4 as shown in C, the expression level of CTSS mRNA in the mice with knocked-down CTSS was significantly decreased compared with that in the control mice; Figure 4 as shown in D, the escape ability of the mice with knocked-down CTSS was enhanced compared with that in the control mice; Figure 4 as shown in E, the exploration ability of the mice with knocked-down CTSS was enhanced after evacuating from the escape platform; Figure 4 as shown in F, the residence time of the mice with knocked-down CTSS in the target quadrant was longer; Figure 4 as shown in G, the latency to find the platform position was shorter in the mice with knocked-down CTSS; Figure 4 as shown in H, the number of times of crossing the escape platform was more in the mice with knocked-down CTSS. Figure 4 It can be seen that knocking down CTSS in the hippocampus of aging mice restored the spatial learning and memory defects.

[0044] APP / PS1 transgenic mice were used as AD model mice, and the selective inhibitor LY 3000328 of CTSS was stereotactically injected through a cannula implanted in the hippocampus to reduce the expression of CTSS. Figure 5 A is the experimental time arrangement; Figure 5 B is the schematic diagram of cannula placement in the hippocampal region; Figure 5 C and 5D show that the fluorescence intensity level of Iba1 decreased in the mice treated with LY300328; Figure 5 E shows that the fluorescence intensity level of 6E10 decreased in the mice treated with LY300328 compared with that in the control mice, Figure 5 F shows that the area of Aβ plaques decreased in the mice treated with LY300328 compared with that in the control mice, Figure 5 G shows that the escape ability of the mice treated with LY300328 was enhanced compared with that in the control mice, Figure 5 H shows that the exploration ability of the mice treated with LY300328 was enhanced after evacuating from the escape platform, Figure 5 I shows that the residence time of the mice treated with LY300328 in the target quadrant was longer, Figure 5 J shows that the latency to find the platform position was shorter in the mice treated with LY300328, Figure 5LY300328 was shown to increase the number of times the treated mice passed through the escape platform. As Figure 5 can be seen, the CTSS inhibitor LY300328 can improve the spatial memory deficit in AD model mice.

[0045] In summary, the expression level of CTSS increases in the aging population and mouse models. By adjusting or inhibiting the expression level of CTSS, the spatial learning and memory levels of mice change. Predicting the decline in behavioral and cognitive functions of neurodegenerative diseases through CTSS levels, and it is possible to improve the cognitive function level of neurodegenerative diseases by adjusting or inhibiting the expression or activity of CTSS. These results indicate that CTSS plays an important regulatory role in cognitive function.

[0046] In the present invention, the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0047] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. Use of cathepsin S in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases.

2. Use of cathepsin S according to claim 1 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, The cathepsin S is used as a marker for detecting cognitive dysfunction or neurodegenerative diseases.

3. Use of cathepsin S according to claim 1 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, The cathepsin S is used for preparing a diagnostic reagent or kit for detecting cognitive dysfunction or neurodegenerative diseases.

4. Use of cathepsin S according to claim 3 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, The diagnostic reagent or kit contains a detection reagent for detecting cathepsin S.

5. Use of cathepsin S according to any one of claims 2 to 4 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, The activity and expression level of the cathepsin S are negatively correlated with neurodegenerative diseases and cognitive dysfunction.

6. Use of cathepsin S according to claim 1 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, Application of the cathepsin S as an intervention target in screening or preparing drugs for treating cognitive dysfunction or neurodegenerative diseases.

7. Use of cathepsin S according to claim 6 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, Overexpression of the cathepsin S is negatively correlated with spatial learning and memory behavior.

8. Use of cathepsin S according to claim 6 or 7 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, The cognitive dysfunction is caused by neurodegenerative diseases.

9. Use of cathepsin S according to claim 8 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, The neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and amyotrophic lateral sclerosis.

10. Use of cathepsin S according to claim 1 in the diagnosis or treatment of cognitive dysfunction or neurodegenerative diseases, characterized in that, The expression level of the cathepsin S is positively correlated with age and aging.

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