Application of a salicornin derivative in the preparation of drugs for treating neurodegenerative diseases

Abstract

This invention discloses the application of a apigenin derivative in the preparation of drugs for treating neurodegenerative diseases. Experiments demonstrate that this apigenin derivative can significantly shorten the platform-finding latency in the Morris water maze test in AD model mice, improving their spatial memory ability. Simultaneously, this derivative can effectively reduce the production and deposition of β-amyloid protein (Aβ) in the brain, significantly improve the cellular senescence phenotype in brain tissue, and inhibit neuroinflammatory responses. This multi-effect mechanism makes this apigenin derivative suitable for the prevention and treatment of age-related and neuroinflammatory neurodegenerative diseases such as Alzheimer's disease.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and in particular relates to the application of a succinin derivative in the preparation of drugs for treating neurodegenerative diseases. Background Technology

[0002] Alzheimer's disease (AD) is a neurodegenerative disease clinically characterized by memory impairment, aphasia, agnosia, visuospatial impairment, executive dysfunction, personality and behavioral changes, and it primarily affects people over 65 years of age. In the early stages of AD, imperceptible pathological changes occur in the brain. With the aging of the global population, the number of AD patients continues to rise.

[0003] Alzheimer's disease (AD) presents with complex pathological phenomena. Brain tissue examinations reveal that patients commonly exhibit senile plaques (SPs) formed by the deposition of large amounts of β-amyloid (Aβ) protein outside brain neurons, neurofibrillary tangles (NFTs) formed by abnormal phosphorylation of tau protein, neuronal loss, neurotrophic disorders, and synaptic loss. With the deepening research into the neurobiological mechanisms of AD, various possible pathogenesis mechanisms have been proposed. The Aβ theory is the mainstream theory for the development of AD. The aggregation of Aβ outside neurons to form senile plaques, also known as amyloid plaques, is one of the most prominent pathological features of AD. This theory clearly states that the disruption of Aβ balance in the brain and the subsequent oligomerization and plaque deposition are the initiating factors triggering the pathological cascade. Studies have shown that the damage of Aβ to the central nervous system is not limited to direct synaptic toxicity, but also lies in the chronic and persistent neuroinflammatory response it induces. Aβ deposition, as a potent immune stimulus, induces pathological overactivation of microglia (immune surveillance cells) and astrocytes (supporting cells) in the brain. Under Aβ stimulation, microglia transform into a pro-inflammatory phenotype, losing their original neuroprotective and debris-clearing functions. Activated glial cells create a highly detrimental pro-inflammatory microenvironment by releasing a series of inflammatory mediators such as TNF-α, IL-1β, IL-6, and reactive oxygen species (ROS). These inflammatory factors not only directly damage neuronal integrity but also further accelerate the pathological modification of tau protein, ultimately leading to the formation and spread of neurofibrillary tangles. This Aβ-triggered inflammatory response is not merely a concomitant phenomenon but a vicious cycle with a self-amplifying effect. As the pathological process progresses, this persistent inflammatory state becomes a core element leading to synaptic dysfunction, neuronal loss, and ultimately cognitive decline.

[0004] Therefore, precise intervention in Aβ-induced neuroinflammatory pathways and regulation of glial cell activation to inhibit the release of harmful factors have become one of the most promising technical approaches for developing novel AD treatments and improving cognitive impairment. This is not only an inevitable choice to block the cascade effects of neurodegenerative diseases, but also a fundamental technical requirement to improve the effectiveness of clinical treatment and enhance patients' quality of life. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides the application of a salicornin derivative in the preparation of a medicament for treating neurodegenerative diseases.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: On one hand, the present invention provides the use of a salicornin derivative and its salts or tautomers in the preparation of a medicament for treating neurodegenerative diseases, wherein the chemical structure of the salicornin derivative is shown in Formula I.

[0007] Formula I Preferably, the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

[0008] Preferably, the drug further comprises a pharmaceutically acceptable carrier.

[0009] Preferably, the dosage form of the drug is selected from any one of oral preparations, intravenous or intramuscular injection preparations, topical administration preparations, and inhalation preparations.

[0010] In the technical solution of the present invention, the drug is used to improve cognitive dysfunction or spatial memory impairment, preferably cognitive dysfunction or spatial memory impairment caused by Alzheimer's disease.

[0011] In the technical solution of the present invention, the drug is used to reduce the deposition of Aβ amyloid protein (Aβ) in the brain.

[0012] In the technical solution of the present invention, the drug is used to delay the aging of brain cells.

[0013] In the technical solution of the present invention, the drug is used to inhibit neuroinflammatory response, including reducing the release of pro-inflammatory cytokines IL-1β and / or IL-6.

[0014] In another aspect, the present invention provides the use of a salicornin derivative and its salts or tautomers in the preparation of a drug for inhibiting the deposition of Aβ amyloid protein (Aβ) in the brain, wherein the chemical structure of the salicornin derivative is shown in Formula I.

[0015] Formula I.

[0016] The above technical solution has the following advantages or beneficial effects: This invention experimentally demonstrates that the apigenin derivative represented by Formula I has significant efficacy in improving symptoms of neurodegenerative diseases. In vivo experimental studies show that the compound of Formula I can effectively reduce the deposition level of amyloid Aβ in brain tissue and reduce the number of SA-β-gal positive cells in the brain, exhibiting a significant effect in delaying neuronal aging. In vitro experiments further confirm that this compound can significantly inhibit the inflammatory response of microglia, reduce the release of pro-inflammatory factors, significantly shorten the platform-finding latency in the Morris water maze test in AD model mice, and improve their spatial memory ability. This multi-effect mechanism makes the compound of Formula I suitable for the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease that are related to aging and neuroinflammation, effectively combating cognitive impairment that occurs during the aging and neurodegenerative disease process. Attached Figure Description

[0017] Figure 1 The figure shows the test results of EW262 improving Morris water maze index in AD mice in Example 1 of this invention.

[0018] Figure 2 This is a graph showing the test results of EW262 reducing Aβ production in AD mice in Example 2 of the present invention.

[0019] Figure 3 This is a diagram showing the test results of EW262 improving cellular senescence in the brains of AD mice in Example 3 of this invention.

[0020] Figure 4 This is a graph showing the test results of EW262 improving the senescence-related phenotype of microglia in Example 4 of the present invention.

[0021] Figure 5 This is a graph showing the test results of EW262 inhibiting microglial inflammatory activation in Example 5 of the present invention. Detailed Implementation

[0022] The following embodiments are merely some, not all, of the embodiments of the present invention. Therefore, the detailed descriptions of the embodiments provided below are not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0023] In this invention, unless otherwise specified, all equipment and raw materials are commercially available or commonly used in the industry. The methods described in the following embodiments are conventional methods in the art, unless otherwise specified.

[0024] Manufacturing example The structure of the salicylic acid derivative (EW262) in the following examples is shown in Formula I, and the synthesis and characterization process is as follows: Formula I (1) Preparation of compound 2

[0025] Under nitrogen protection, tert-butyldimethylchlorosilane (TBSCl, 11.6 g, 1.00 eq) and N,N-diisopropylethylamine (DIEA, 20.0 g, 2.00 eq) were added to a solution of compound 1 (ferulic acid, 15.0 g, 1.00 eq) in N,N-dimethylformamide (DMF, 150 mL) at 0 °C. The mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 1:1, R...). f = 0.7), the results showed that compound 1 had reacted completely.

[0026] The reaction mixture was washed with water (120 mL) and extracted with dichloromethane (100 mL × 3). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, compound 2 was obtained as a pale yellow oil (18.0 g, crude product).

[0027] The obtained compound 2 was confirmed by liquid chromatography-mass spectrometry and proton nuclear magnetic resonance spectroscopy.

[0028] (2) Preparation of compound 3

[0029] Under nitrogen protection, N,N-dimethylformamide (83.0 mg, 0.10 eq) and oxalyl chloride (2.88 g, 2.00 eq) were added to a solution of compound 2 (3.50 g, 1.00 eq) in dichloromethane (DCM, 35.0 mL) at 0 °C. The mixture was stirred at 25 °C for 3 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry, and the results showed that compound 2 had reacted completely.

[0030] After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 3, which was a yellow oily substance (2.60 g, crude product).

[0031] The obtained compound 3 was confirmed by liquid chromatography-mass spectrometry analysis.

[0032] (3) Preparation of compound 6

[0033] Under nitrogen protection, at 0 °C, compound 4 (salicylic acid, 809 mg, 1.00 mg) was subjected to nitrogen treatment. eq Compound 3 (2.60 g, 2.50 g) was added to a pyridine (26.0 mL) solution. eq A solution of dichloromethane (DCM, 2.60 mL) was prepared. The mixture was stirred at 25 °C for 16 hours under nitrogen protection. TLC (petroleum ether: ethyl acetate = 3:1, R) was performed. f = 0.66) indicates that compound 3 reacted completely. The reaction mixture was washed with citric acid (20 mL * 3), and the aqueous phase was extracted with ethyl acetate (30 mL * 3). The organic layer was washed with saturated brine (30 mL) and dried over Na2SO4. The solvent was removed by filtration under reduced pressure. The product (SiO2, petroleum ether:ethyl acetate = 5:1 to 3:1) was purified and separated by silica gel column chromatography to give compound 6 as a yellow solid (1.10 g, 2.02 mmol, yield 63.5%).

[0034] (4) Preparation of compound EW262

[0035] At 0 °C, glacial acetic acid (AcOH, 22.1 mg, 0.2 mg) was added to a tetrahydrofuran (THF solution, 10.0 mL) solution of compound 6 (1.00 g, 1.00 eq). eq ) and tetrabutylammonium fluoride (TBAF 1 M, 3.67 mL, 2.00 eq The mixture was stirred at 0°C for 1 hour. TLC (petroleum ether: ethyl acetate = 3:1, R) f = 0.41) indicates that compound 6 reacted completely. The reaction mixture was washed with water (10.0 mL*2), and the aqueous phase was extracted with ethyl acetate (10.0 mL*3). The organic layer was washed with saturated brine (15.0 mL) and dried over Na2SO4. The solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (SiO2, petroleum ether:ethyl acetate = 3:1 to 1:1) to give compound EW262 as a yellow solid (400 mg, 929 μmol, yield 50.6%). 1 H NMR: ET52299-28-P1N (400 MHz, DMSO) δ ppm 3.85 (s, 3 H)6.71 - 6.79 (m, 2 H) 6.84 (d, J = 8.07 Hz, 1 H) 7.13 - 7.28 (m, 3 H) 7.45 (d, J= 1.47 Hz, 1 H) 7.56 - 7.69 (m, 3 H) 7.81 (d, J = 15.77 Hz, 1 H) 8.14 (d, J =6.97 Hz, 2 H) 9.77 (s, 1 H) 12.87 (s, 1 H). Example 1 This example demonstrates that the apigenin derivative (EW262) prepared in Manufacturing Example 1 can improve the learning and memory abilities of AD mice, as detailed below: Materials and Methods 1.1.1 Animals and Grouping Forty 9-month-old WT mice and 40 5×FAD transgenic mice (AD mice) were selected, and the mice were divided into 4 groups: The WT + Veh group consisted of normal mice. The WT + EW262 group was the group of normal WT mice that were given the drug; The 5×FAD + Veh group was the AD model mouse group. The 5×FAD + EW262 group was the 5×FAD mouse administration group (20 mice in each group, 10 males and 10 females).

[0036] EW262 was administered via gavage at a dose of 50 mg / kg / day for 90 consecutive days. The Morris water maze behavioral test was then used to examine the effects of EW262 on the learning and cognitive function of 5×FAD mice.

[0037] 1.1.2 Water Maze Experiment This experiment uses the classic Morris water maze test procedure, which consists of two parts: a positioning and navigation test and a space exploration test. The experiment lasts for 9 days, with the space exploration test added on the 9th day.

[0038] 1.1.3 Data Analysis All experimental data are expressed as mean ± standard error. Two-way ANOVA was used to analyze multiple groups of results, and Holm-Šídák's multiple comparisons test was used for post-hoc testing. A p-value < 0.05 was considered statistically significant between groups.

[0039] 1.2 Results from Figure 1The experimental results showed that after 8 days of training, the escape latency of all four groups of animals in this navigation experiment was shortened, indicating that all mice could successfully complete the spatial learning task of the water maze. Escape latency was used as the detection index. From the third day onwards, compared with the 5×FAD group, the escape latency of the WT + Veh group and the WT + EW262 group was significantly reduced. From the fifth day of the navigation experiment, the escape latency of the 5×FAD + EW262 group was significantly shorter than that of the 5×FAD group. The ability of the drug-treated mice to find the platform continuously improved with the increase of training sessions. The latency performance of the 5×FAD group was worse than that of the WT + Veh group and the WT + EW262 group, suggesting a decline in learning and memory ability in the 5×FAD mice, which better simulated the learning and memory impairment of AD. The latency of the drug-treated groups was significantly different from that of the model group, indicating that EW262 administration significantly improved the learning and memory abilities of AD mice.

[0040] As can be seen from this example, administration of EW262 can reduce cognitive impairment in 5×FAD mice.

[0041] Example 2 This example demonstrates that the apigenin derivative (EW262) prepared in Manufacturing Example 1 can reduce Aβ formation, as detailed below: 2.1 Materials and Methods 2.1.1 Obtaining experimental animal samples Forty 9-month-old WT mice and 40 5×FAD transgenic mice (AD mice) were selected, and the mice were divided into 4 groups: The WT + Veh group consisted of normal mice. The WT + EW262 group was the group of normal WT mice that were given the drug; The 5×FAD + Veh group was the AD model mouse group; The 5×FAD + EW262 group was the 5×FAD mouse administration group (20 mice in each group).

[0042] EW262 was administered via gavage, with a daily dose of 50 mg / kg / day for 90 consecutive days. After the administration, behavioral tests were performed, and the mice were anesthetized, perfused with saline, and the left hemisphere of the mice was collected and separated.

[0043] 2.1.2 Cryosection of brain tissue For the obtained hemispheres, Aβ plaque deposition in the mouse cortex and hippocampus was examined: The left hemisphere was fixed in pre-cooled 4% paraformaldehyde for 24 h, then dehydrated in 30% sucrose for 48 h. When the brain tissue settled to the bottom of the sucrose solution, the hemisphere was removed, embedded in OCT, and flash-frozen in liquid nitrogen at -80°C. The brain tissue was then cut into 30 μm coronal sections and placed in cryoprotectant. The brain tissue was labeled with its number and the experimental date on a 24-well plate, and 1 ml of cryoprotectant was added to each well. The cut brain slices were collected sequentially into the 24-well plate using a fine brush. Collection began from the first well, with one slice per well until the first row of wells was filled. Collection then resumed from the first well of the first row, with three slices per well, and so on, until all the required brain slices were collected. The brain slices were then collected in cryoprotectant and stored at -20°C. Antifreeze formulation: 50% PBS + 30% ethylene glycol + 20% glycerol.

[0044] 2.1.3 Immunofluorescence staining of frozen sections of brain tissue Brain slices from the same location were retrieved during staining and washed off the protective solution in 1×PBS. The slices were then placed in permeation blocking buffer (0.3% Triton X-100 and 5% BSA in 1×PBS) and permeated on a shaker at room temperature for 60 min. The slices were then incubated overnight at 4°C on a shaker with primary antibody diluted in the permeation blocking buffer (6E10 dilution, 1:500). The next day, the slices were incubated again. Afterward, the slices were placed in secondary antibody diluted in 1×PBS and Hoechst 33342 (1:1000 dilution) and incubated on a shaker at room temperature in the dark for 2 h. The slices were then washed in 1×PBS in the dark, removed, and placed on a glass slide. Mounting medium was added, and the slide was sealed with a coverslip. The stained brain slices were then photographed using an Olympus IX71 inverted fluorescence microscope.

[0045] 2.1.4 Data Analysis All experimental data are expressed as mean ± standard error. Two-way ANOVA was used to analyze multiple groups of results, and Tukey's multiple comparisons test was used for post-hoc testing. A p-value < 0.05 was considered statistically significant between groups.

[0046] 2. Results Amyloid plaque deposition (Aβ) is an important pathological marker indicating brain pathological changes in Alzheimer's disease. Therefore, in this study, we further investigated whether EW262 reduced Aβ deposition in the brains of 5×FAD mice. The results showed that no Aβ plaque deposition was observed in the cortex and hippocampus of mice in the WT + Veh and WT + EW262 groups, while significant plaque deposition was observed in the brains of 5×FAD model mice. Compared with the 5×FAD + Veh group, EW262 administration significantly reduced the area of ​​Aβ plaques in the hippocampus and cortex of 5×FAD mice, and significantly improved the plaque deposition in the brains of 5×FAD patients. Figure 2 .

[0047] As can be seen from this example, administration of EW262 can improve AD pathology by reducing Aβ deposition.

[0048] Example 3 This embodiment demonstrates that the apigenin derivative (EW262) prepared in Manufacturing Example 1 can improve cellular senescence in the brains of AD mice. The specific process is as follows.

[0049] 3.1 Materials and Methods 3.1.1 SA-β-gal staining For SA-β-gal staining, the frozen brain sections were first thawed for 20 min, and then washed three times with 1×PBS. An appropriate volume of β-galactosidase staining fixative was added, enough to fully cover the tissue, and fixed at room temperature for at least 15 min. The brain slices were then washed three times with 1×PBS, each time for at least 5 min. The PBS was removed, and an appropriate amount of staining working solution was added. The staining working solution was prepared using the Beyotime kit: 10 μl of β-galactosidase staining solution A + 10 μl of β-galactosidase staining solution B + 930 μl of β-galactosidase staining solution C + 50 μl of X-gal. The solution was incubated overnight at 37 ℃, and then washed with 70% ethanol. After washing the brain slices three times with 1×PBS, they were observed under a regular optical microscope.

[0050] 3.1.2 Data Analysis All experimental data are expressed as mean ± standard error. Two-way ANOVA was used to analyze multiple groups of results, and Dunnett's multiple comparisons test was used for post-hoc testing. A p-value < 0.05 was considered statistically significant between groups.

[0051] 3.2 Results Cellular senescence is a cellular stress and damage response involving multiple biological pathways, such as DNA damage response, cell cycle arrest, senescence-associated secretory phenotype (SASP), senescence-related mitochondrial dysfunction, autophagy dysfunction, and nutritional and stress signals. Senescence is the most severe stage of neurodegenerative diseases, leading to the failure of the body's overall repair mechanisms and ultimately resulting in the aging of the body. Therefore, in this study, SA-β-gal staining was used to further investigate whether EW262 reduces cellular senescence in the brains of 5×FAD mice.

[0052] The results showed that the levels of SA-β-gal positive expression in the brains of mice in the WT + Veh and WT + EW262 groups were significantly lower than those in the 5×FAD + Veh and 5×FAD + EW262 groups. This indicates that severe cellular senescence occurred in the brains of 5xFAD mice. Compared with the 5×FAD + Veh group, the levels of SA-β-gal positive expression in the cerebral cortex and hippocampus of mice in the 5×FAD + EW262 group were significantly reduced.

[0053] As can be seen from this example, administration of EW262 can significantly improve cellular senescence in the brains of 5×FAD mice and delay the aging process of mice. Example 4 This embodiment demonstrates that the apigenin derivative (EW262) prepared in Manufacturing Example 1 can improve the senescence-related phenotype of microglia. The specific process is as follows.

[0054] 4.1 Materials and Methods 4.1.1 Cells and Experimental Treatment To leverage the characteristic of erytoposide stimulation inducing significant cellular senescence in HMC3 cells, human microglia (HMC3) cells were cultured in DMEM, seeded into 12-well plates, and cultured for 24 hours. Etoposide (1 μM) was then added for 24 hours of stimulation, followed by incubation with EW262 (10 μM) for 24 hours. RNA was extracted from the cells using Trizol, and the expression of relevant inflammatory factors was detected by qPCR.

[0055] 4.1.2 Data Analysis All experimental data are expressed as mean ± standard error. One-way ANOVA was used to analyze multiple groups of results, and Tukey's multiple comparisons test was used for post-hoc testing. A p-value < 0.05 was considered statistically significant between groups.

[0056] 4.2 Results Cellular senescence can lead to the formation of the senescence-associated secretory phenotype (SASP) and promote the expression of various pro-inflammatory factors. In this embodiment, the inventors induced HMC3 cell senescence using etoposide and evaluated the effect of EW262 on the senescence-associated secretory phenotype by detecting the expression levels of the inflammatory factors IL-6 and IL-1β. The results showed that the expression of IL-6 and IL-1β in HMC3 cells was significantly increased after etoposide stimulation; after EW262 treatment, the expression of both inflammatory factors was significantly decreased, such as... Figure 4 As shown.

[0057] As can be seen from this embodiment, EW262 can effectively improve the senescence-related secretory phenotype of microglia and reduce the inflammatory response generated during cell senescence.

[0058] Example 5 This embodiment demonstrates that the apigenin derivative (EW262) prepared in Manufacturing Example 1 can inhibit microglial cell inflammatory activation, and the specific process is as follows.

[0059] 5.1 Materials and Methods 5.1.1 Cells and Experimental Treatment LPS stimulation was used to induce significant inflammatory activation in BV2 microglia. BV2 cells were cultured in DMEM medium and seeded into 12-well plates for 24 hours. Subsequently, except for the blank control group, all other groups were treated with lipopolysaccharide (LPS) at a final concentration of 300 ng / mL to induce cellular inflammatory responses. Simultaneously, the LPS+EW262 group received 10 μM EW262, the LPS+juglansin group received an equal concentration of juglansin, and the LPS+ferulic acid group received an equal concentration of ferulic acid; all groups were incubated for 24 hours.

[0060] After the culture was completed, the cell culture supernatant was collected, and after centrifugation to remove cell debris, the contents of TNF-α and IL-6 in the supernatant were detected using an ELISA kit.

[0061] 5.1.2 ELISA Detection The levels of TNF-α and IL-6 in cell culture supernatant were detected using a commercially available ELISA kit. Standards and samples were prepared according to the kit instructions, added to the ELISA plate, and the absorbance was measured at 450 nm. The concentrations of TNF-α and IL-6 were calculated based on the standard curve.

[0062] 5.1.3 Data Analysis All experimental data are expressed as mean ± standard error. One-way ANOVA was used to analyze multiple sets of results, and Tukey's multiple comparisons test was used for post-hoc verification. p A value <0.05 is considered to indicate a significant difference between groups.

[0063] 5.2 Results Neuroinflammation is an important pathological feature of neurodegenerative diseases such as Alzheimer's disease. Activated microglia can release a large number of pro-inflammatory factors, thereby exacerbating nerve damage. In this embodiment, the inventors used an LPS-induced BV2 cell inflammation model and evaluated the anti-inflammatory activity of EW262 by detecting the levels of TNF-α and IL-6 in the culture supernatant using ELISA.

[0064] The results showed that, compared with the control group, the levels of TNF-α and IL-6 in the culture supernatant of BV2 cells were significantly increased after LPS stimulation. Treatment with EW262 significantly reduced the release of both inflammatory factors. Further comparison revealed that, under the same experimental conditions, EW262 was more effective than the succinate and ferulic acid monomer treatment groups in reducing TNF-α and IL-6 levels. Figure 5 .

[0065] As demonstrated in this embodiment, administration of EW262 significantly reduces the release of inflammatory factors. EW262 exhibits significantly enhanced anti-inflammatory activity, and its ability to inhibit the release of inflammatory factors is significantly superior to that of the parent compounds, apigenin and ferulic acid.

[0066] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The use of a succinin derivative and its salts or tautomers in the preparation of a medicament for treating neurodegenerative diseases, characterized in that, The chemical structure of the salicylic acid derivative is shown in Formula I. Equation I.

2. The application according to claim 1, characterized in that, The neurodegenerative diseases mentioned include Alzheimer's disease, dementia, and Parkinson's disease.

3. The application according to claim 1, characterized in that, The drug also contains a pharmaceutically acceptable carrier.

4. The application according to claim 1, characterized in that, The dosage form of the drug is selected from any one of oral preparations, intravenous or intramuscular injection preparations, topical administration preparations, and inhalation preparations.

5. The application according to claim 1, characterized in that, The drug is used to improve cognitive impairment or spatial memory impairment.

6. The application according to claim 5, characterized in that, The drug is used to improve cognitive impairment or spatial memory impairment caused by Alzheimer's disease.

7. The application according to claim 1, characterized in that, The drug is used to reduce the deposition of Aβ amyloid protein (Aβ) in the brain.

8. The application according to claim 1, characterized in that, The drug is used to slow down the aging of brain cells.

9. The application according to claim 1, characterized in that, The drug is used to suppress neuroinflammatory responses, including reducing the release of pro-inflammatory cytokines IL-1β and / or IL-6.

10. The use of a succinin derivative and its salts or tautomers in the preparation of a medicament for inhibiting the deposition of Aβ amyloid protein (Aβ) in the brain, characterized in that, The chemical structure of the salicylic acid derivative is shown in Formula I. Equation I.

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