Application of STM2457 in the preparation of drugs for preventing and treating Alzheimer's disease

Abstract

The present invention discloses the use of STM2457 in the preparation of drugs for the prevention and treatment of Alzheimer's disease, and belongs to the field of biomedicine technology. In view of the problem that there is currently a lack of effective therapeutic drugs for Alzheimer's disease, the present invention finds that STM2457 inhibits Mettl3-mediated N6-adenylate methylation (m 6 A) modification level, thereby reducing the level of amyloid deposition, inhibiting neuroinflammatory response and improving cognitive function, can be used to prepare medicines or health foods for preventing and treating Alzheimer's disease or other neuroinflammatory related diseases. The present invention verifies the therapeutic effect of STM2457 in Alzheimer's disease model mice. STM2457 has an inhibitory effect on amyloid deposition and neuroinflammation in Alzheimer's disease model mice, and has an improving effect on learning and memory disorders in Alzheimer's disease model mice. STM2457 can significantly inhibit the production of amyloid deposition and reduce the level of neuroinflammation in Alzheimer's disease model mice, and significantly improve the cognitive memory disorders in Alzheimer's disease model mice.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and more specifically, to the use of STM2457 in preparing a drug for preventing and treating Alzheimer's disease. Background Art

[0002] Alzheimer's disease is a neurodegenerative disease of the elderly, characterized by memory loss and cognitive decline. The most notable pathological features of Alzheimer's patients are the massive accumulation of amyloid Aβ in the brain and the presence of neuroinflammation, which triggers the death of a large number of neurons. Therefore, understanding how to control Aβ deposition and neuroinflammation is critical for the prevention and treatment of neurodegenerative diseases and delaying the onset of the disease. Previous studies have shown that the brain m 6 A modification level and Mettl3 protein expression level are abnormal, but for Mettl3-mediated m 6 The specific role of A modification in Alzheimer's disease is still unclear.

[0003] m 6 A modification is the most abundant and widely studied type of modification on messenger RNA (mRNA). In mammalian cells, about 20% to 40% of transcripts contain mRNA. 6 A modification. Mettl3 belongs to the Mettl methyltransferase family, which catalyzes m 6 A methylation reaction occurs. Studies have shown that the loss of Mettl3 will lead to m 6 A levels almost completely disappeared. Studies have conducted transcriptome sequencing and m 6 A methylation sequencing, through disease-related enrichment analysis of differentially expressed genes, found that a large number of genes related to Alzheimer's disease have mRNAs in both brain organoids and human brains. 6 A modification, which suggests m 6 A may play a very important role in the occurrence and development of AD. 6 A methylation sequencing revealed that mRNAs in the cortex and hippocampus of APP / PS1 transgenic mice 6 A methylation level was increased and the expression level of Mettl3 was increased.

[0004] STM2457, structural formula is C 25 H 28 N6O2( Figure 1), inhibits the activity of METTL3 methyltransferase by binding to the S-adenosylmethionine binding site of METTL3. Therefore, STM2457 is a specific inhibitor of METTL3 and has been used in acute myeloid leukemia research. Studies have found that when leukemia model mice were treated with STM2457, STM2457 inhibited the proliferation and expansion of cancer cells, reduced the number of leukemia cells in the mouse bone marrow and spleen, and significantly prolonged the life span of mice, and this drug had no toxic side effects. Many studies have found that STM2457 has a good effect on liver cancer and non-small cell lung cancer. STM2457 is currently highly safe in both intraperitoneal injection and oral administration in animal models, and the role of STM2457 in the treatment of neurodegenerative diseases has not been reported, and no clinical trials have been retrieved. Summary of the invention

[0005] The purpose of the present invention is to overcome the current lack of effective therapeutic drugs for Alzheimer's disease. On the one hand, the present invention provides the use of STM2457 in the preparation of drugs for the treatment of Alzheimer's disease.

[0006] The present invention also provides the use of STM2457 in preparing a drug for inhibiting neurodegenerative diseases associated with amyloid protein deposition.

[0007] The present invention also provides the use of STM2457 in preparing a drug for treating neuroinflammation caused by amyloid protein.

[0008] The present invention also provides the use of STM2457 in preparing medicines and / or health products for improving memory or cognitive function.

[0009] Preferably, STM2457 reduces m in the brain of Alzheimer's disease model mice 6 A modification level, inhibiting the production of amyloid protein deposition, thereby inhibiting and improving cognitive function.

[0010] The present invention uses m in Alzheimer's disease model mice 6 A methylation sequencing, Western Blot, immunofluorescence staining, qPCR, behavioral studies, etc. detected the presence of amyloid protein deposition, increased Mettl3 expression level, and m 6 Increased A modification levels lead to a phenotype of cognitive dysfunction in mice.

[0011] The present invention administered STM2457 to Alzheimer's disease model mice by intraperitoneal injection every day for two consecutive months. Western Blot, immunofluorescence staining, and Dot Blot detected that STM2457 could inhibit the production of amyloid protein and neuroinflammation. The results showed that STM2457, as an inhibitor of Mettl3, could inhibit the production of amyloid protein and neuroinflammation by reducing the level of m in the brain. 6 A modification level, thereby significantly inhibiting the production of amyloid protein, significantly improving neuroinflammation, and significantly improving the cognitive memory function of Alzheimer's mice.

[0012] Therefore, STM2457 reduces the brain m 6 A modification level, thereby inhibiting the level of amyloid protein and improving cognitive function, can be used to prepare medicines or health foods for preventing and treating Alzheimer's disease or other neurodegenerative diseases. Therefore, the following applications of STM2457 are all within the scope of protection of the present invention.

[0013] The use of STM2457 in the preparation of medicines and / or health products for preventing and treating Alzheimer's disease or other neurodegenerative diseases and / or improving memory, STM2457 inhibits m 6 A modification levels, thereby inhibiting the level of amyloid protein and improving cognitive function.

[0014] Theoretically, all drugs containing STM2457 are within the protection scope of the present invention; the STM2457 can be extracted using conventional extraction methods in the art.

[0015] The present invention provides a drug for preventing and treating Alzheimer's disease, which comprises STM2457. Further, the drug further comprises a pharmaceutically acceptable excipient or carrier.

[0016] Specifically, the pharmaceutical preparation is a tablet, a hard capsule, a soft capsule, a powder, a tincture, an oral solution, a pill or an injection.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] The present invention discloses the use of STM2457 (Mettl3 inhibitor) in the preparation of a drug for Alzheimer's disease, and specifically discloses that STM2457 inhibits Mettl3-mediated N6-adenosine methylation (m 6A) modification level, thereby reducing the level of amyloid deposition, inhibiting neuroinflammatory response and improving cognitive function, can be used to prepare medicines or health foods for preventing and treating Alzheimer's disease or other neuroinflammatory related diseases. The present invention verifies the therapeutic effect of STM2457 in Alzheimer's disease model mice. STM2457 has an inhibitory effect on the level of amyloid in Alzheimer's disease model mice, and has an improving effect on the learning and memory disorders of Alzheimer's disease model mice. STM2457 can significantly reduce the level of amyloid and neuroinflammatory levels in Alzheimer's disease model mice, and significantly improve the cognitive memory disorders of Alzheimer's disease model mice. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the chemical structure formula of STM2457.

[0020] Figure 2 Evaluation of amyloid beta (Aβ) and cognitive memory impairment in Alzheimer's disease model mice.

[0021] Figure 3 Changes in Mettl3 expression levels and m 6 Changes in A-related enzymes.

[0022] Figure 4 The brain of Alzheimer's disease model mice 6 A Modification sequencing analysis.

[0023] Figure 5 STM2457 inhibits m 6 A modification level.

[0024] Figure 6 STM2457 reduces amyloid levels and neuroinflammation in Alzheimer's mice.

[0025] Figure 7 STM2457 can improve cognitive memory impairment in Alzheimer's disease mice. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0027] Example 1 5xFAD model mice simulate the pathological characteristics and cognitive memory impairment of Alzheimer's disease.

[0028] 1. Methods

[0029] The Alzheimer's disease model mice used in this study were 5xFAD model mice purchased from Jax Lab, and the mouse strain number was: Jax#034848.

[0030] Immunofluorescence staining: Mice were anesthetized with isoflurane and perfused with 1xPBS and then cold perfused with 4% paraformaldehyde (PFA). The brains were dissected and fixed with 4% PFA for 2 days. After complete dehydration in 30% sucrose at 4°C for 3 days, 30μm sagittal sections were cut using a freezing microtome. The sections were stored in the preservation solution at -20°C. The brain sections containing the hippocampus region were washed three times with PBS for staining. Blocking solution (containing 3% goat serum in PBS and 0.1% Triton x-100) was used for 1 hour at room temperature on a shaker, and then incubated with primary antibodies at 4°C overnight. The next day, the samples were washed with PBS, then incubated with secondary antibodies and DAPI for 1 hour at room temperature, and then washed again and mounted with mounting medium to be mounted on slides. Images were taken using an Olympus confocal microscope. All photos were taken under the same conditions and settings.

[0031] Morris Water Maze (MWM): The MWM was conducted in a circular, water-filled bathtub (120 cm in diameter) with visual cues outside the maze, the water was rendered opaque by covering its surface with titanium dioxide, and the bathtub was divided into four virtual quadrants. The MWM was divided into two phases: training and testing. During the training phase, an invisible escape platform (11 cm in diameter) was located 1 cm below the water surface. Mice entered the water maze from four different starting positions in the pool. The time it took for each animal to reach the escape platform was recorded, and each animal was trained four times per day for four consecutive days. The testing phase was conducted 24 h after the last training session, during which the platform was removed and the proportion of the time the mouse spent swimming and exploring in the four virtual quadrants within 120 s was measured, as well as the first time to reach the location of the previously placed escape platform and the total number of times the platform position was crossed. The trial was videotaped and analyzed using MazeScan software.

[0032] Novel object recognition: This test is based on the fact that mice prefer to touch novel objects. In the experiment, mice were placed in an illuminated white plastic box (60cmx60cmx30cm), monitored by an overhead camera, and analyzed by an automatic tracking system (San DiegoInstruments, CA). On the first day, two objects of the same shape were placed in the test box, and the mice were placed in the box to explore freely for 10 minutes. After 24 hours, one of the objects was replaced with another object of a different shape. The mice were placed in the box again for 10 minutes to explore the objects, and the time spent exploring the two objects was evaluated and the ratio was calculated.

[0033] Y-maze spontaneous alternation: three identical opaque arms (35 cm long, 8 cm wide, and 8 cm high) at 120 degrees to each other were used, with spatial cues at the far end. The continuous spontaneous alternation test was based on the natural tendency of mice to explore new environments. Mice were placed in the Y-maze, facing the wall of a randomly selected arm, and were free to explore the three arms in the Y-maze for 8 minutes. In general, mice tended to explore the arms that had been most recently and not visited, forming alternations between the three arms, which relied on their spatial working memory. The percentage of spontaneous alternation was used as a measure, and all the alternations (i.e., each time the mouse explored three arms in succession) were divided by all possible alternations (i.e., the total number of arms entered minus 2), and then multiplied by 100.

[0034] Statistical analysis: Data are expressed as mean ± SEM and analyzed using GraphPad Prism software. Unpaired t-test was used to determine the differences between two groups; two-way ANOVA and Bonferroni multiple comparison test were used to determine the differences between multiple groups. P < 0.05 was considered statistically significant.

[0035] 2. Results

[0036] Aβ immunofluorescence staining was performed on 5xFAD mice aged 2, 3, 4, and 5 months to detect the level of Aβ amyloid deposition. The results showed that 5-month-old 5xFAD mice had more amyloid protein deposition ( Figure 2 a). Behavioral tests were performed on 5-month-old 5xFAD mice (AD) and wild-type mice (WT). The results of the water maze test showed that 5xFAD mice took longer to reach the platform, stayed in the quadrant where the platform was located for less time, and crossed the platform less frequently, while the total movement distance and speed remained unchanged ( Figure 2 b-1h). The spontaneous alternation test in the Y-maze showed that the spontaneous alternation rate of 5xFAD mice was lower, suggesting working memory impairment ( Figure 2 i-2j). The novel object recognition experiment showed that 5xFAD mice spent less time exploring new objects than wild-type mice ( Figure 2 k-2m). Overall, the results suggest that 5xFAD mice mimic the typical pathological features of Alzheimer's disease, namely amyloid deposition and cognitive memory impairment.

[0037] Example 2 The expression level of Mettl3 is increased in 5xFAD mice.

[0038] 1. Methods

[0039] Western Blot: Total protein was extracted from the dissected brain hippocampus tissue after rapid freezing in liquid nitrogen. The tissue was ground on ice with RIPALysis buffer and then transferred to a centrifuge tube. The supernatant was collected and quantified by BCA protein assay. According to the molecular weight of the target protein, the protein was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) at different concentrations of separation gel and then transferred to a nitrocellulose membrane. The membrane was blocked with 5% skim milk in TBST for 1 hour at room temperature and incubated with the primary antibody at 4°C overnight. After washing 3 times with TBST, it was incubated with the enzyme-labeled secondary antibody at room temperature for 1 hour. The membrane was rinsed 3 times with TBST and incubated with ultrasensitive ECL. The protein bands were displayed using a molecular imaging system, and the band intensity was measured using ImageJ software.

[0040] 2. Results

[0041] In order to determine the changes in the expression level of Mettl3 in 5xFAD mice, Western Blot analysis was performed by extracting proteins from the cerebral cortex (CTX), olfactory bulb (OB), and hippocampus (HIPPO) of wild-type mice and 5xFAD mice at 2 months (2M), 3 months (3M), and 5 months (5M). The results showed that the level of Mettl3 increased in the hippocampus tissue of 5-month-old mice ( Figure 3 a-3d). The experiment also detected m in the hippocampus tissue of 2-month-old, 3-month-old, and 5-month-old rats. 6 A The expression of other related enzymes Mettl14 and Fto was examined and the results showed that the protein levels of Mettl14 and Fto did not change ( Figure 3 e-3g).

[0042] Taken together, these results indicate that the expression level of Mettl3 is increased in the hippocampal tissue of Alzheimer's disease model mice, while Mettl14 and Fto remain unchanged, suggesting that Mettl3 may be involved in the amyloid protein deposition process and cognitive memory impairment in Alzheimer's disease model mice.

[0043] Example 3 m in the brain of Alzheimer's disease model mice 6 A modification level increased

[0044] 1. Methods

[0045] m 6 A-IP-Seq:

[0046] After extracting total RNA from the sample using Trizol, mRNA was isolated using mRNA purification kit (Ambion, 61006) and DNA was removed using DNase I. mRNA was incubated at 94°C for 1 min with RNA fragmentation reagent (Ambion, AM8740) to fragment into 100 nt fragments and purified by ethanol precipitation for m 6 A-MeRIP. 10 μgm 6 A polyclonal antibody (Synaptic Systems, 202003) and 40 μl Dynabeads TM Protein A (Invitrogen, 10001D) was incubated in 500μl IPP buffer (150mM NaCl, 0.1% NP-40, 10mM Tris-HCl, pH 7.4) at room temperature for 1 hour. RNA was heated at 75℃ for 5min and immediately placed on ice. After cooling, 5μg RNA was mixed with antibody-magnetic beads and incubated at 4℃ for 4 hours. The magnetic beads were retained, the supernatant was discarded, and the magnetic beads were washed 5 times with IPP buffer. RNA was eluted from the magnetic beads with 300μl 0.5mg / ml N6-Methyladenosine shaken at room temperature for 1 hour. The supernatant after elution was extracted with chloroform, ethanol precipitated, dissolved in RNase Free Water, and used for subsequent experiments. m 6 A The analysis of sequencing data was based on the published literature Donimissini et al, Geula et al (2015) and Lence et al (2016). 6 A total number of peaks and distribution characteristics, m 6 A modified gene names and enriched signaling pathways, m 6 Amotif. Cross-analyze the results with RNA sequencing analysis to obtain the relationship with gene expression (upregulation and downregulation) and screen for specific target genes.

[0047] 2. Results

[0048] To determine whether 5xFAD mice have m 6 A modified abnormality was observed in 5-month-old 5xFAD mice. 6 A sequencing analysis. The results showed that there were mRNAs in the CDS region and 3'UTR region of the mRNA of 5xFAD mice. 6 Increased levels of A modification ( Figure 4 a-4c). for m 6 KEGG analysis of genes with increased A levels revealed that 6 Genes upregulated by A modification are closely related to neurodegenerative diseases and Alzheimer's disease ( Figure 4 d-4e). GO enrichment analysis found that m 6 A modified upregulated genes are related to synaptic assembly and axon generation of neurons ( Figure 4 f). Transcriptome sequencing analysis revealed that compared with WT mice, the expression levels of 769 genes in 5xFAD mice were increased, and the expression levels of 360 genes were decreased ( Figure 4 g). GO enrichment analysis found that up-regulated genes were related to functions such as inflammatory response, while down-regulated genes were related to functions such as neuronal synaptic assembly ( Figure 4 h-4i). and m 6 A further analysis of the upregulated genes revealed that m 6 A affects the expression levels of genes related to synaptic assembly, aging, microglia activation, neuronal apoptosis, etc. Figure 4 j).

[0049] In summary, the mRNA in 5xFAD mice 6 A modification is changed and the gene m associated with Alzheimer's disease 6 A modification level increased, suggesting that it may be m 6 Increased levels of A modification affect the pathological process of Alzheimer's disease.

[0050] Example 4 STM2457 significantly reduces the m 6 A modification level

[0051] 1. Methods

[0052] Preparation and use of STM2457: STM2457 was purchased from MCE, catalog number: HY-134836. STM2457 was dissolved in saline. 5xFAD mice were divided into two groups and injected with saline and STM2457 solution respectively for 60 days (50 mg / kg, intraperitoneal injection, once a day), and then the two groups of mice were killed for experiments, with 4 mice in each group for each experiment.

[0053] m 6 A dot blot:

[0054] Total RNA extraction and qRT-PCR: Total RNA from cells and tissues was extracted using TRIzol reagent according to the manufacturer's protocol, and the concentration was determined by Nanodrop spectrophotometer 2000 (Thermo Fisher Scientific). RNA was denatured by treatment with formaldehyde, formamide and high temperature, and then cooled on ice. Prepare Hybond N+ membranes of appropriate size and place them on the 96-well dot blot instrument, and assemble the instrument as required. After adding DEPC water to the wells to wash the instrument, RNA samples were added to the wells in sequence, and the liquid in the wells was removed by vacuum. Remove the Hybond N+ membrane and crosslink at 80°C or UV crosslink at 254nm. Remove the crosslinked Hybond N+ membrane, block it, and incubate with the corresponding primary and secondary antibodies respectively. After washing, it can be exposed to ECL colorimetric solution. Methylene blue staining can be used as a control for equal loading of RNA.

[0055] 2. Results

[0056] Alzheimer's mice were injected with STM2457 at 3 months of age for two consecutive months. The mice were killed at 5 months of age, and total RNA was extracted. Dot Blot was then used to detect m 6 The results showed that after SRTM2457 treatment, compared with the control group, the brain m 6 The level of A modification was significantly reduced ( Figure 5 a-5b). Western Blot was performed to detect the level of Mettl3 after extracting the protein in the mouse brain. It was found that STM2457 did not affect the protein level of Mettl3, which is consistent with previous research reports ( Figure 5 c-5d). In summary, STM2457 can significantly inhibit the m 6 A modification level.

[0057] Example 5 STM2457 significantly improves pathological features of Alzheimer's disease mice

[0058] 1. Methods

[0059] Immunofluorescence staining: Mice were anesthetized with isoflurane and perfused with 1xPBS and then cold perfused with 4% paraformaldehyde (PFA). The brains were dissected and fixed with 4% PFA for 2 days. After complete dehydration in 30% sucrose at 4°C for 3 days, 30 μm sagittal sections were cut using a freezing microtome. The sections were stored in the preservation solution at -20°C. The brain sections containing the hippocampal region were washed three times with PBS for staining. Blocking solution (containing 3% goat serum in PBS and 0.1% Triton x-100) was used for 1 hour at room temperature on a shaker, and then incubated with primary antibodies at 4°C overnight. The next day, the samples were washed with PBS, then incubated with secondary antibodies and DAPI for 1 hour at room temperature, and then washed again and mounted with mounting medium to be made into slides. Images were taken using an Olympus confocal microscope. All pictures were taken under the same conditions and settings, and the fluorescent area was counted using ImageJ. Four to six brain slices were counted for each mouse.

[0060] 2. Results

[0061] In order to determine whether STM2457 can affect the level of amyloid deposition and neuroinflammation in the brains of Alzheimer's mice, the two groups of mice were perfused and frozen, and then immunofluorescence staining was performed. Compared with the control group (AD+Vehicle), the STM2457-treated group (AD+STM2457) showed a decrease in the Aβ staining area in the cortex and hippocampus of the mouse brain ( Figure 6 a-6c), and we used Western Blot to detect the intermediate products sAPPβ and CTFβ in the amyloid production pathway. The results showed that the sAPPβ and CTFβ protein levels in the STM2457 treatment group were significantly reduced ( Figure 6 d-6f). In order to detect the effect of STM2457 on the level of neuroinflammation in Alzheimer's disease, immunofluorescence staining was performed using the astrocyte marker GFAP and microglia marker Iba1. The results showed that the signal area of ​​neuroinflammation markers GFAP and microglia was reduced ( Figure 6 g-6i).

[0062] These results indicate that STM2457 treatment of Alzheimer's mice can reduce amyloid levels and neuroinflammation levels in the brain.

[0063] Example 6 STM2457 significantly improves cognitive dysfunction in Alzheimer's disease mice

[0064] 1. Methods

[0065] Morris Water Maze (MWM): The MWM was conducted in a circular, water-filled bathtub (120 cm in diameter) with visual cues outside the maze, the water was rendered opaque by covering its surface with titanium dioxide, and the bathtub was divided into four virtual quadrants. The MWM was divided into two phases: training and testing. During the training phase, an invisible escape platform (11 cm in diameter) was located 1 cm below the water surface. Mice entered the water maze from four different starting positions in the pool. The time it took for each animal to reach the escape platform was recorded, and each animal was trained four times per day for four consecutive days. The testing phase was conducted 24 h after the last training session, during which the platform was removed and the proportion of the time the mouse spent swimming and exploring in the four virtual quadrants within 120 s was measured, as well as the first time to reach the location of the previously placed escape platform and the total number of times the platform position was crossed. The trial was videotaped and analyzed using MazeScan software.

[0066] Novel object recognition: This test is based on the fact that mice prefer to touch novel objects. In the experiment, mice were placed in an illuminated white plastic box (60cmx60cmx30cm), monitored by an overhead camera, and analyzed by an automatic tracking system (San DiegoInstruments, CA). On the first day, two objects of the same shape were placed in the test box, and the mice were placed in the box to explore freely for 10 minutes. After 24 hours, one of the objects was replaced with another object of a different shape. The mice were placed in the box again for 10 minutes to explore the objects, and the time spent exploring the two objects was evaluated and the ratio was calculated.

[0067] Y-maze spontaneous alternation: three identical opaque arms (35 cm long, 8 cm wide, and 8 cm high) at 120 degrees to each other were used, with spatial cues at the far end. The continuous spontaneous alternation test was based on the natural tendency of mice to explore new environments. Mice were placed in the Y-maze, facing the wall of a randomly selected arm, and were free to explore the three arms in the Y-maze for 8 minutes. In general, mice tended to explore the arms that had been most recently and not visited, forming alternations between the three arms, which relied on their spatial working memory. The percentage of spontaneous alternation was used as a measure, and all the alternations (i.e., each time the mouse explored three arms in succession) were divided by all possible alternations (i.e., the total number of arms entered minus 2), and then multiplied by 100.

[0068] Statistical analysis: Data are expressed as mean ± SEM and analyzed using GraphPad Prism software. Unpaired t-test was used to determine the differences between two groups; two-way ANOVA and Bonferroni multiple comparison test were used to determine the differences between multiple groups. P < 0.05 was considered statistically significant.

[0069] 2. Results

[0070] The results of the Y-maze test showed that the spontaneous alternation rate of AD mice treated with STM2457 was significantly increased compared with that of AD mice treated with saline, while the total number of entries into the exploratory arm remained unchanged ( Figure 7 a-7b). The novel object recognition task test showed that the STM2457 treatment group spent more time exploring novel objects ( Figure 7 c-7d). During the training phase of the Morris water maze test, the STM2457-treated group took a shorter time to reach the platform than the saline-treated group ( Figure 7 e). During the test phase, the STM2457-treated group had a reduced time to reach the platform for the first time, a longer stay in the target quadrant, an increased number of platform crossings, and a total swimming distance and swimming time that remained unchanged ( Figure 7 f-7k).

[0071] Taken together, these results indicate that STM2457 can improve cognitive memory impairment in Alzheimer's disease mice.

[0072] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. Application of STM2457 in the preparation of drugs for preventing and treating Alzheimer's disease.

2. The use according to claim 1, characterized in that: STM2457 inhibits the brain's m 6 A modification level, thereby reducing the level of amyloid protein deposition, inhibiting neuroinflammatory response and improving cognitive function.

Images