Application of FGF2 signaling pathway inhibitor in treatment of neurodegenerative diseases

Abstract

The invention discloses application of an FGF2 signaling pathway inhibitor in treatment of neurodegenerative diseases, and relates to the technical field of biological medicines. The invention provides an application of an FGF2 signaling pathway inhibitor in treatment of neurodegenerative diseases by researching the action relation between FGF2 and the neurodegenerative diseases (such as Alzheimer's disease), and a large number of experiments find that the FGF2 signaling pathway inhibitor can reverse the occurrence of the neurodegenerative diseases induced by FGF2. A new theoretical basis and a new treatment technology thereof are provided for neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to an application of an FGF2 signaling pathway inhibitor in treating neurodegenerative diseases. Background Art

[0002] Neurodegenerative diseases are a class of neurological diseases characterized by progressive neuronal dysfunction, which are common in people aged 60 years and over. Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis. Although their causes are complex and diverse, these diseases often show common symptoms in clinical practice, including dementia, memory loss, depression and cognitive dysfunction. The age-standardized prevalence of dementia in people over 60 years old is about 5-7% worldwide. Limited research from clinics studying dementia estimates that the prevalence of AD in the 45 to 64 age group is 15%-65% per 100,000 patients.

[0003] In the case of acute injury or COVID-19 infection, inflammation significantly upregulates the levels of inflammatory factors IL-6 / IL-17D / IL-1B and FGF2 (fibroblast growth factor 2), causing nuclear hnRNPA1 to partially translocate to the cytoplasm and be degraded through the ATG16L1-mediated autophagy pathway. The reduction of hnRNPA1 further leads to the downregulation of ATG16L1α through skippable exon events, thereby weakening the level of autophagy.

[0004] So far, no one has studied or published the relationship between the inflammatory signaling factor FGF2 and neurodegenerative diseases (such as Alzheimer's disease). Therefore, studying the expression level of the inflammatory signaling factor FGF2 and the effects of its signaling pathway inhibitors on neurodegenerative diseases will provide a new treatment idea and important approach for neurodegenerative diseases such as Alzheimer's disease (AD). Summary of the invention

[0005] The present invention provides an application of an FGF2 signaling pathway inhibitor in treating neurodegenerative diseases, which is specifically achieved through the following technologies.

[0006] The present invention provides an application of an FGF2 signaling pathway inhibitor in the preparation of a drug for treating neurodegenerative diseases. The FGF2 signaling pathway inhibitor is a compound that inhibits FGF2 gene expression or inhibits the functional activity of FGF2 receptors.

[0007] This paper explores how inflammation-induced FGF2 (fibroblast growth factor 2) acts as a potential risk factor for the onset of Alzheimer's disease (AD), and ultimately finds that it affects autophagy and AD pathology through a multi-step mechanism. By injecting the inflammatory signal FGF2 factor into the tail vein of mice, the present invention found that the upregulation of FGF2 phenotypically ultimately caused neuronal disarray in the hippocampus of mice, promoted the accumulation of APP / Aβ deposits in the hippocampus, decreased autophagy levels, and significantly aggravated AD pathology. This mechanism explains how inflammation-induced FGF2 upregulation acts as a basic driving force to damage the autophagy factor ATG16L1α, thereby weakening the autophagy capacity and triggering AD neuropathology.

[0008] The present invention also reverses the effects of FGF2 on AD neurodegenerative lesions by injecting FGF2 into the tail vein of mice and using Erdafitinib, an inhibitor of the FGF2 signaling pathway, after the injection of FGF2. The neurobehavioral changes of mice were detected, specifically by conducting T-maze, Y-maze and water maze experiments. It was found that the FGF2 signaling pathway inhibitor can reverse Alzheimer's lesions, indicating a new role of the drug in the treatment of AD.

[0009] The preliminary experiments of the present invention have proved that COVID-19-induced inflammation and trauma such as AKI (acute kidney injury) induce FGF2 production, and FGF2 induces hnRNPA1 protein nucleocytoplasmic shuttling; hnRNPA1 protein in the cytoplasm directly binds to the autophagic protein ATG16L1, inducing autophagic degradation of hnRNPA1 protein. Downregulation of hnRNPA1 protein in the nucleus affects the alternative splicing of ATG16L1 protein and the level of ATG16L1α; tail vein injection of FGF2 will induce a decrease in autophagy level and affect the accumulation of APP / Aβ deposits. In the case of COVID-19 and renal injury, inflammatory factors IL-6 / IL-17D / IL-1B and growth factor FGF2 are upregulated. Upregulated FGF2 causes hnRNPA1 to translocate from the nucleus to the cytoplasm and colocalize with LC3B. hnRNPA1 translocated to the cytoplasm directly interacts with ATG16L1 and is degraded by autophagy. hnRNPA1 in the nucleus affects the level of autophagy through alternative splicing of ATG16L1α. Finally, FGF2 induces hnRNPA1 to export from the nucleus, affecting the pathological phenotype of Alzheimer's disease.

[0010] FGF2 also promotes the translocation of some hnRNPA1 proteins from the nucleus to the cytoplasm, thereby reducing brain autophagy. Based on these findings, we propose that inflammatory signal-induced FGF2 upregulation may impair autophagy by weakening the expression of the autophagy component ATG16L1α, ultimately leading to APP / Aβ deposition in the hippocampus and AD neuropathological changes.

[0011] Furthermore, the FGF2 signaling pathway inhibitor is Erdafitinib.

[0012] Furthermore, the FGF2 signaling pathway inhibitor is an RNA that knocks down FGF2 gene expression; for example, including but not limited to siRNA, shRNA, etc.

[0013] Erdafitinib is currently generally used as a cancer treatment drug, mainly for the treatment of locally advanced or metastatic urothelial carcinoma, bladder cancer and lung cancer. The present invention accidentally discovered through the above research that Erdafitinib can also be used to treat neurodegenerative diseases.

[0014] Furthermore, the raw materials of the neurodegenerative disease therapeutic drug also include pharmaceutically acceptable carriers and / or excipients.

[0015] Furthermore, the carrier includes one or more of a solvent, a polymer and a liposome.

[0016] Furthermore, the auxiliary material includes one or more of a diluent, an excipient and a stabilizer.

[0017] Furthermore, the neurodegenerative disease is Alzheimer's disease.

[0018] The present invention also provides a drug for treating neurodegenerative diseases, wherein the drug comprises any one of the above-mentioned FGF2 signaling pathway inhibitors.

[0019] Compared with the prior art, the present invention is beneficial in that: by studying the interaction between FGF2 and neurodegenerative diseases (such as Alzheimer's disease), the present invention provides an application of an FGF2 signaling pathway inhibitor in the treatment of neurodegenerative diseases, thereby providing a new theoretical basis and new treatment technology for neurodegenerative diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the hematoxylin and eosin (H&E) staining result of Example 1.

[0021] Figure 2 This is the tissue immunofluorescence imaging result of Example 1.

[0022] Figure 3 and Figure 4 The Western blot results of Example 1 are shown in FIG.

[0023] Figure 5 This is the fluorescence detection result of Example 1.

[0024] Figure 6The immunofluorescence analysis results of Example 1 are shown in FIG.

[0025] Figure 7-10 This is the result of Western blot analysis of Example 1.

[0026] Fig.11 This is a schematic diagram of the verification test process of Example 2 for the role of FGF2 in Alzheimer's disease (AD) neuropathy.

[0027] Figure 12-14 These are the test results of the Y-maze, T-maze and Morris water maze of Example 2, respectively.

[0028] Fig.15 This is the test result of the probe experiment in Example 2.

[0029] Fig.16 and 17 They are the test results of the number of times the mouse platform crosses and the target quadrant residence time in Example 2. DETAILED DESCRIPTION

[0030] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] The test methods described in the following examples are all conventional techniques in the art, or are based on the conditions recommended by the manufacturers unless otherwise specified; the reagents, materials and instruments used without indicating the manufacturer are all conventional products that can be purchased commercially.

[0032] Example 1: FGF2 leads to the accumulation of APP / Aβ deposits in the hippocampus, thereby inducing neuropathological changes in Alzheimer's disease (AD)

[0033] 1. Western blot

[0034] (1) Pretreatment of target protein: Select SDS-PAGE gel of appropriate concentration for electrophoresis according to the size of target protein (APP / hnRNPA1 and corresponding internal reference protein), prepare 1× electrophoresis buffer and pour into the electrophoresis tank. Mix the newly prepared protein sample evenly (if the protein sample is stored at 4°C, it needs to be placed at room temperature for 10 min before mixing evenly), and centrifuge at 12000 rpm for 1 min;

[0035] (2) Electrophoresis: Add the protein sample to the gel tank and add a protein marker to mark the protein size. Perform constant current electrophoresis with a current of 10 mA per gel. Cut the gel block containing the target protein according to the protein marker and place it in 1× wet transfer buffer.

[0036] (3) Transfer: Cut the appropriate PVDF / NC membrane and slightly larger filter paper according to the size of the gel block. Soak the PVDF / NC membrane in methanol, prepare the transfer device, and soak the clamps in wet transfer buffer. Rinse the PVDF / NC membrane in wet transfer buffer and then place it on the wet filter paper.

[0037] Gently place the gel block on the PVDF / NC membrane, making sure there are no bubbles; then place the wet filter paper on the gel block and press it to remove the bubbles; put the assembled transfer clip into the transfer instrument, making sure that one side of the PVDF / NC membrane faces the negative electrode and the gel block faces the positive electrode. Do not move the position of the membrane, gel block and filter paper during the assembly process. Transfer the membrane at a current of 350 mA for 1 h.

[0038] (4) Incubate with primary antibody: Place the PVDF membrane containing the target protein in blocking solution and block at room temperature for 1 h. After blocking, place the PVDF membrane in TBST and wash on a shaker at room temperature for 5 min.

[0039] Dilute the primary antibody with 5% BSA at an appropriate ratio, cut off the excess membrane according to the size of the target protein, place the membrane in the diluted primary antibody, and incubate at 4°C overnight or 37°C for 2 h.

[0040] (5) Incubate with secondary antibody: Place the membrane in TBST and wash on a shaker at room temperature for 4 times, 5 min each time. Dilute the appropriate secondary antibody according to the secondary antibody instructions, generally at a ratio of 1:5000. Incubate with the corresponding secondary antibody according to the properties of the primary antibody and incubate on a shaker at room temperature for 2 h.

[0041] (6) Color development: Place the membrane in TBST and wash it on a shaker at room temperature for 4 times, 5 min each time. Prepare a color development solution and soak the membrane in it. Use X-ray film to develop in a dark room. The development results are scanned with a scanner, and the images can be used for subsequent experimental analysis and mapping.

[0042] 2. Paraffin sectioning and staining

[0043] (1) Construction of animal model: C57BL / 6 mice of about 2 months old were selected and fasted for 12 h and 8 h before surgery. The mice were randomly divided into FGF2 treatment group and control group (the number of mice in each group was greater than 5).

[0044] FGF2-treated group: 5 ng / g FGF2 was injected continuously for three days.

[0045] Control group: injected with 0.9% saline.

[0046] FGF2+Erdafitinib group: After the injection of FGF2, the FGFR inhibitor Erdafitinib was gavaged into the mice at a dose of 10 mg / kg.

[0047] (2) Pretreatment of kidney and brain tissue samples: C57BL / 6 mice were killed, kidney and brain tissues were removed, and they were washed thoroughly with PBS to remove residual blood. The tissues were placed in pre-cooled 4% paraformaldehyde (PFA) and fixed overnight at 4°C.

[0048] After fixation, the tissues were washed thoroughly with PBS and dehydrated sequentially with graded ethanol (70%, 85%, 95%, and 100%) for 5 min each step.

[0049] The dehydrated tissue was first treated in a 1:1 xylene-ethanol mixed solution for 1 h, and then transparentized in pure xylene twice, each time for 1 h.

[0050] (3) Paraffin-embedded tissue samples and sections: The cleared tissue was placed in a gradient paraffin-xylene mixed solution (25%, 50%, and 75%) in sequence, with each step soaking for 30 min, and then immersed in pure paraffin twice, each time for 30 min, to achieve sufficient penetration.

[0051] After embedding the tissue in paraffin, it was quickly cooled on a freezing table and oriented in an embedding mold.

[0052] The paraffin blocks were cut into sections with a thickness of 5-8 µm using a microtome. The sections were placed in a drop of distilled water on a slide, developed at 42°C and dried naturally.

[0053] (4) Dewaxing: The dried tissue sections were treated in xylene twice for 10 min each time, and then rehydrated stepwise through a gradient ethanol series (100%, 95%, 85%, and 70%) and distilled water, each step for 5 min.

[0054] (5) H&E staining (hematoxylin and eosin staining)

[0055] Hematoxylin staining: Stain the sections with hematoxylin for 3-5 min, wash off excess stain with tap water, differentiate with hematoxylin differentiation solution for a few seconds, rinse with tap water, then blue with hematoxylin bluing solution for a few seconds, and rinse with running water for a few seconds.

[0056] Eosin staining: Dehydrate the sections with gradient alcohol (85% ethanol → 95% ethanol) and stain them in eosin staining solution for 5 min.

[0057] Dehydration and sealing: The slices were placed in anhydrous ethanol ① for 5 min, anhydrous ethanol ② for 5 min, anhydrous ethanol ③ for 5 min, n-butanol for 5 min, xylene ① for 5 min, and xylene ② for 5 min to make them transparent. The slices were taken out of xylene and dried slightly, and then sealed with neutral gum. Interpretation of results: The nucleus is blue and the cytoplasm is red.

[0058] Finally, the sections were mounted with neutral gum for microscopic observation.

[0059] 3. Tissue Immunofluorescence Imaging

[0060] (1) Antigen repair: Place the dewaxed and rehydrated paraffin sections in pre-heated antigen repair solution (pH = 6.0 citric acid solution), then place them in a sterilizer and treat them in a high pressure cooker at 105°C for 5 min.

[0061] After antigen repair, place in a beaker and cool in water, and then proceed with subsequent immunofluorescence operations after cooling to room temperature.

[0062] (2) Immunofluorescence:

[0063] The sections were treated with 1% Triton X-100 at room temperature for 20 min and then washed three times with PBS for 3 min each time.

[0064] Block with 5% BSA at 37°C for 1 h, and remove serum.

[0065] The antibody was incubated at 4°C overnight, rewarmed at room temperature for 30 min, and washed 5 times with PBS, each time for 3 min.

[0066] The following steps were protected from light. The fluorescent labeled secondary antibody was incubated at 37℃ for 1.5 h, and then washed 5 times with PBS, 3 min each time; the corresponding fluorescent secondary antibody was incubated at 37℃ for 1 h, and then washed 5 times with PBS.

[0067] The slides were sealed with anti-fading sealing solution containing DAPI and observed and photographed under a fluorescence microscope.

[0068] 4. Nuclear and cytoplasmic separation and immunoblotting

[0069] (1) Wash the tissue twice with pre-cooled PBS to remove blood stains. After adding buffer A, place on ice for 15 minutes. Add one twentieth volume of buffer B, vortex for 10 seconds, and place on ice for 1 minute.

[0070] (2) Then centrifuge at 1000 g for 5 min at 4°C and separate the supernatant and precipitate.

[0071] ① Centrifuge the supernatant at 4°C, 12,000 g for 5 min, and continue to collect the supernatant to obtain the cytoplasm;

[0072] ② Vortex the precipitate vigorously for 10 seconds, return it to the ice bath for 10 minutes, and repeat three times; then centrifuge it at 4°C, 12,000 g for 5 minutes, take the supernatant, and obtain the cell nuclei.

[0073] All components were snap-frozen in liquid nitrogen and stored at −80°C until further immunoblot analysis.

[0074] 5. Research and verification of the mechanism of FGF2's involvement in AD neuropathology

[0075] In order to verify the role of FGF2 in AD neuropathology by inhibiting autophagy, the present invention further analyzed the related histological changes and molecular mechanisms.

[0076] like Figure 1 The results of H&E staining showed that the neurons in the CA1 and CA3 regions of the hippocampus of the FGF2-treated group were disordered on the 4th day, while the control group mice injected with 0.9% NaCl saline showed normal neurons. The mouse tissues were collected on the 4th day after injection for subsequent experiments.

[0077] Figure 2 The results showed tissue immunofluorescence imaging, which showed that FGF2 treatment led to a significant accumulation of APP / Aβ protein deposits in the mouse brain.

[0078] Figure 3 Western blot further confirmed the significant increase in Aβ oligomer levels in the brains of FGF2-treated mice. Figure 4 Western blot showed that the level of hnRNPA1 in the cell nucleus was significantly reduced.

[0079] Figure 5 Fluorescence detection showed that FGF2 treatment led to a significant nuclear-cytoplasmic translocation of hnRNPA1 protein in hippocampal neurons.

[0080] Figure 6 Immunofluorescence analysis further found that the LC3B-II bodies in the CA1 and CA3 regions of the hippocampus of mice treated with FGF2 were significantly reduced.

[0081] Figure 7-10 Western blot analysis showed that the levels of LC3B-II and ATG16L1α in the brains of mice treated with FGF2 decreased significantly from day 4 compared with those in the control group.

[0082] These results indicate that FGF2 treatment leads to a significant decrease in the level of autophagy in the brain, which may cause abnormal splicing of ATG16L1 through the downregulation of hnRNPA1, thereby leading to autophagy defects.

[0083] Example 2: Intervention effect of FGF2 signaling inhibitor Erdafitinib and its reversal of cognitive function

[0084] 1. Construction of animal model

[0085] C57BL / 6 mice of about 2 months old were selected and fasted for 12 hours and 8 hours before surgery. The mice were randomly divided into FGF2 treatment group and control group (the number of mice in each group was greater than 5).

[0086] FGF2-treated group: 5 ng / g FGF2 was injected continuously for three days.

[0087] Control group: injected with 0.9% saline.

[0088] FGF2+Erdafitinib group: After the injection of FGF2, the FGFR inhibitor Erdafitinib was gavaged into the mice at a dose of 10 mg / kg.

[0089] 2. Mouse Behavior Analysis

[0090] (1) Y-maze test

[0091] In this example, spatial memory in exploratory behavior was evaluated by a Y-maze experiment. The Y-maze consisted of three identical arms, each 40 cm long, 10 cm wide, and 15 cm high, connected to each other at an angle of 120°. Before the test, the mice were acclimated in the test room for at least 30 min to reduce stress behavior.

[0092] During the test, each mouse was placed at the end of one of the arms and allowed to freely explore the maze for 8 min. The percentage of spontaneous alternations (i.e., alternation score) was calculated based on the order of arm entries. This score was calculated by dividing the number of entries into a new arm (different from the previous one) by the total number of arm transitions, providing an index of spatial working memory.

[0093] (2) T-maze test

[0094] To further assess spatial memory, a T-maze test was also performed. This test used an apparatus made of gray plastic, including a start arm (38 cm long, 10 cm wide, and 25 cm high) and two goal arms (each 30 cm long, 9 cm wide, and 25 cm high).

[0095] In the test, mice were returned to the start arm for the choice phase, when both goal arms were open. If the mouse chose the goal arm opposite to the one it chose during the forced phase, a spontaneous alternation was recorded. The spontaneous alternation rate was calculated to measure the ability of mice to remember and explore a new spatial environment.

[0096] (3) Morris water maze test

[0097] Morris water maze test was used to evaluate the spatial learning and memory ability of mice in the experimental and control groups. Titanium dioxide was added to the water until the platform was hidden.

[0098] The experiment was divided into two phases: training phase and platform removal test. In the training phase, the water maze was divided into 4 quadrants, and the platform was 1 cm below the water surface in the second quadrant. Mice were trained for 5 consecutive days, starting from the 4 quadrants in a pseudo-random manner. Four times a day, each lasting 60 seconds, and the latency to find the hidden platform was recorded. The water temperature was maintained at 22±1℃, and the external visual cues remained unchanged.

[0099] Mice were pseudo-randomly placed in one of the three quadrants without a platform and faced the pool wall to start each trial, which lasted 60 seconds. Mice that did not find the platform were guided to the platform and stayed on it for 10 seconds to reinforce memory. If the mouse did not find the platform for more than 60 seconds, its escape latency was assumed to be 60 seconds; the swimming path of each mouse was analyzed. On day 6, a platform removal test was performed, in which mice swam freely for 60 seconds without the platform. Videos were recorded, and the time spent in the target quadrant and the number of entries into the target quadrant were analyzed.

[0100] The above Example 1 has found that FGF2 rises in inflammation, causing hnRNPA1 to be exported from the nucleus, resulting in a decrease in the level of ATG16L1α, affecting the level of autophagy and leading to AD. Next, this example analyzes the effect of FGF2 treatment on the morphology of mouse hippocampus and cortex tissue at different time points through H&E staining. Figure 1 By injecting FGF2 in C57BL / 6 mice, the tissue structure of the CA3 region, CA1 region, DG, and cortex of the hippocampus in the control group and on the 4th day after FGF2 treatment was demonstrated. The results showed that in the control group, the tissue structure of each brain region was normal, the neurons were closely arranged, and the morphology was regular. However, after FGF2 treatment, obvious tissue structural changes appeared in the CA1 region, CA3 region, and cortex of the hippocampus. These changes may be related to the role of FGF2 in neuronal survival and function, and suggest the potential impact of FGF2 in neurodegenerative diseases.

[0101] In order to prove that FGF2 may play a role in Alzheimer's disease (AD) neuropathy by inhibiting autophagy, the present invention administered FGF2 to adult C57BL / 6J mice via tail vein injection for three consecutive days at a dose of 5 ng per gram of body weight per day, i.e., the FGF2-treated group. The injected mice were then used for analysis. Fig.11 shown.

[0102] Fig.12 and Fig.13The effects of FGF2 treatment on spatial learning and memory performance were evaluated using the Y-maze and T-maze tests, respectively. The results showed that the FGF2-treated group showed significant cognitive decline in these tests compared to the control group.

[0103] To further explore the spatial memory deficit, Fig.14 Morris water maze was used to test the effect of FGF2 on cognitive function of mice. The escape latency of the FGF2-treated group was significantly prolonged on the 4th and 5th days.

[0104] Fig.15 The results are shown in the probe test (after removing the platform), which is similar to the experimental method of the first 5 days, but the platform is removed and the mice are observed for the time they stay in the target quadrant and the number of times they cross the platform. The control mice showed a clear preference for the original platform location, while the FGF2-treated mice performed poorly in locating the platform area.

[0105] Similar results are also reflected in Fig.16 and Fig.17 These results indicate that FGF2 treatment significantly impaired the spatial learning and memory abilities of mice.

[0106] The above specific embodiments describe the implementation of the present invention in detail, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the claims and technical concept of the present invention, the technical solution of the present invention can be modified and changed in many simple ways, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. Use of an FGF2 signaling pathway inhibitor in the preparation of a drug for treating neurodegenerative diseases, characterized in that: The FGF2 signaling pathway inhibitor is a compound that inhibits FGF2 gene expression or inhibits the functional activity of FGF2 receptor.

2. The use of the FGF2 signaling pathway inhibitor according to claim 1 in the preparation of a drug for treating neurodegenerative diseases, characterized in that: The FGF2 signaling pathway inhibitor is Erdafitinib.

3. The use of claim 1 in preparing a drug for treating neurodegenerative diseases, characterized in that: The FGF2 signaling pathway inhibitor is an RNA that knocks down the expression of the FGF2 gene.

4. Use of the FGF2 signaling pathway inhibitor according to claim 1 in the preparation of a drug for treating neurodegenerative diseases, characterized in that: The raw materials of the neurodegenerative disease therapeutic drug also include pharmaceutically acceptable carriers and / or excipients.

5. Use of the FGF2 signaling pathway inhibitor according to claim 4 in the preparation of a drug for treating neurodegenerative diseases, characterized in that: The carrier includes one or more of a solvent, a polymer and a liposome.

6. Use of the FGF2 signaling pathway inhibitor according to claim 4 in the preparation of a drug for treating neurodegenerative diseases, characterized in that: The auxiliary materials include one or more of diluents, excipients and stabilizers.

7. Use of the FGF2 signaling pathway inhibitor according to claim 1 in the preparation of a drug for treating neurodegenerative diseases, characterized in that: The neurodegenerative disease is Alzheimer's disease.

8. A drug for treating neurodegenerative diseases, characterized in that: The medicine comprises the FGF2 signaling pathway inhibitor according to any one of claims 1 to 7.

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