Application of DGAT1 specific oral inhibitor in neurodegenerative diseases

Abstract

The invention relates to the technical field of treatment of neurodegenerative diseases, in particular to application of a DGAT1 specific oral inhibitor in neurodegenerative diseases, and the DGAT1 specific oral inhibitor is used for treating pathological tau protein related neurodegenerative diseases including Pick disease (PiD), Alzheimer's disease (AD), progressive suprakaryotic paralysis (PSP), cortical basal degeneration (CBD), silver granulopathy (AGD), familial tau proteopathy and the like. According to the application of the DGAT1 specific oral inhibitor in the treatment of the tau protein disease, the DGAT1 inhibitor is PF-04620110 (DGAT1 specificity) or PF-06865571 (DGAT1 and DGAT2 specificity). According to the application of the DGAT1 specific oral inhibitor in neurodegenerative diseases, the DGAT1 inhibitor can effectively penetrate through a blood-brain barrier through oral administration, the activity of a key enzyme DGAT1 for synthesizing triglyceride in glial cells is specifically inhibited, then abnormal accumulation of lipid droplets in the glial cells can be remarkably reduced through the targeted inhibition effect, and the DGAT1 specific oral inhibitor can be applied to neurodegenerative diseases. The normal physiological function is recovered.

Description

Technical Field

[0001] The present invention relates to the technical field of neurodegenerative disease treatment, and in particular to the application of a DGAT1 specific oral inhibitor in neurodegenerative diseases. Background Art

[0002] Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Its pathological hallmarks include extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein. However, another pathological hallmark, the formation of lipid inclusions or lipid droplets in various neuronal cell types, suggests that lipid metabolism is disrupted in the AD brain. Lipid metabolism is crucial for brain energy supply and normal function. Neutral lipids such as triglycerides (TAGs) are the main components of lipid droplets and are increased in neurological diseases and aging. DGAT1 / 2 are transmembrane proteins localized to the endoplasmic reticulum (ER) that catalyze the final step in TAG synthesis. DGAT1 is exclusively present in the ER and has broad substrate specificity, while DGAT2 is localized to both the ER and lipid droplets and is the primary TAG biosynthetic enzyme. DGAT1-deficient mice are thin and resistant to high-fat diet-induced obesity, but DGAT2-deficient mice die shortly after birth.

[0003] In recent years, DGAT1 inhibitors have attracted extensive attention due to their potential to regulate lipid metabolism, among which PF-04620110 and PF-06865571 (Ervogastat) are two representative drug candidates. PF-04620110 is a potent and selective DGAT1 inhibitor (IC 50 19nM), which can significantly reduce intestinal lipid absorption, but its clinical application is relatively limited due to certain gastrointestinal side effects at high doses. In contrast, PF-06865571, as a new generation inhibitor (IC 50 <10nM), and by optimizing its structure (benzimidazole skeleton) and liver targeting, it reduces liver fat while also reducing intestinal adverse reactions, showing better therapeutic prospects in metabolic diseases such as NASH. Furthermore, PF-06865571 has the ability to simultaneously target both DGAT1 and DGAT2. Given the key role of DGAT1 in lipid droplet formation and lipid metabolism regulation, this class of inhibitors may affect AD-related tau pathology and neurodegeneration by regulating neuronal lipid homeostasis, providing new ideas for AD treatment.

[0004] While numerous studies have explored the role of DGAT1 inhibition in metabolic diseases, its role in tauopathy, a key hallmark of AD, remains unclear. Using the PS19 mouse model of tauopathy, researchers investigated the effects of DGAT1 on tau pathology and neurodegeneration. Results showed that DGAT1 deficiency reduced lipid droplet formation, alleviated tau pathology, and slowed disease progression, potentially mitigating neuronal ferroptosis caused by lipid metabolism disturbances through the SREBP pathway. These findings suggest that DGAT1 inhibition may be a promising therapeutic strategy for AD.

[0005] To this end, a DGAT1-specific oral inhibitor is designed for use in neurodegenerative diseases to provide a technical solution to the above-mentioned technical problems. Summary of the Invention

[0006] Based on this, it is necessary to provide a DGAT1-specific oral inhibitor for use in neurodegenerative diseases to address the above technical problems, so as to solve the technical problems raised in the above background technology.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] Application of DGAT1-specific oral inhibitors in the treatment of tauopathies.

[0009] As a preferred embodiment of the use provided by the present invention, the DGAT1 inhibitor is PF-04620110 or PF-06865571.

[0010] As a preferred embodiment of the application provided by the present invention, the DGAT1 inhibitor is PF-04620110, which has a chemical structure of a pyridoxaline derivative, a molecular formula of C20H18F3N3O3, and a molecular weight of 405.37.

[0011] As a preferred embodiment of the application provided by the present invention, the DGAT1 inhibitor is PF-06865571, which has a chemical structure of a benzimidazole derivative, a molecular formula of C23H25F3N4O3, and a molecular weight of 462.47.

[0012] DGAT1 inhibitors are used to treat pathological tau protein-related neurodegenerative diseases, including Pick disease (PiD), Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), familial tauopathy, etc.

[0013] As a preferred embodiment of the use provided by the present invention, a therapeutically effective amount of a DGAT1 inhibitor is administered to a patient.

[0014] As a preferred embodiment of the application provided by the present invention, the application steps are as follows:

[0015] PS19 mice were administered DGAT1 inhibitors, either PF-04620110 or PF-06865571, via stainless steel gavage.

[0016] Oral administration daily for 10 weeks;

[0017] Pathological evaluation was performed on PS19 mice after the end of drug administration.

[0018] As a preferred embodiment of the application provided by the present invention, the pathological assessment includes changes in the volume of the hippocampus and piriform cortex, the level of phosphorylated tau protein, the accumulation of lipid droplets in brain glial cells, and the function of microglia.

[0019] It can be seen without a doubt that the above-mentioned technical solution of this application can definitely solve the technical problem to be solved by this application.

[0020] At the same time, through the above technical solutions, the present invention has at least the following beneficial effects:

[0021] 1. The DGAT1-specific oral inhibitor provided by the present invention is used in the treatment of neurodegenerative diseases. Oral administration of the DGAT1 inhibitor can effectively penetrate the blood-brain barrier and specifically inhibit the activity of DGAT1, a key enzyme in triglyceride synthesis in glial cells. The targeted inhibition can significantly reduce the abnormal accumulation of lipid droplets in glial cells (especially microglia) and restore their normal physiological function.

[0022] 2. The functionally normalized microglia of the present invention can enhance the ability to recognize and clear pathological proteins (including disseminated phosphorylated tau protein) while maintaining selective protection of healthy neurons; this dual regulatory effect can effectively block the pathological progression of tau disease and show good therapeutic potential.

[0023] 3. The present invention reduces tau pathology and inhibits DGAT1 to reduce the accumulation of phosphorylated tau, delaying the formation of NFTs, thereby protecting neurons, alleviating brain atrophy, maintaining the structural integrity of the hippocampus and cortex, alleviating neuroinflammation, reducing microglial activation and lipid droplet accumulation, and improving the microenvironment.

[0024] 4. The DGAT1-specific oral inhibitors of the present invention are highly safe: DGAT1 inhibitors have been proven safe in clinical trials for metabolic diseases and can be rapidly applied to the treatment of tauopathy. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following is a brief introduction to the drawings required for use in the description of the embodiments. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0026] Figure 1 Schematic diagram of the expression changes of DGAT1 in the pathological process of tau disease and its effect on tau pathology;

[0027] Figure 2 Schematic diagram of the effect of the DGAT1 inhibitor treatment of the present invention on brain pathology in PS19 transgenic mice. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0029] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0030] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features and technical solutions therein may be combined with each other.

[0031] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, it does not require further definition or explanation in subsequent drawings.

[0032] Reference Figure 1-Figure 2 , DGAT1-specific oral inhibitors are used in neurodegenerative diseases.

[0033] Figure 1Figure 3. (a) Cluster heat map of changes in DGAT1 expression levels across Braak stages; (b) Representative images of colocalization of DGAT1 immunostaining (green) and X34 amyloid staining (red) in brain tissues of patients with Alzheimer's disease (Scale bar = 20 μm); (c) qPCR quantitative analysis of DGAT1 mRNA expression in PS19 transgenic mice at different ages (3, 6, and 9 months); (d) Survival analysis curves of PS19 mice in the TD1+ / + and TD1+ / − groups (n = 18 or 24) (TD1:PS19::DGAT1); (e) Representative images of hematoxylin-eosin (H&E) staining of brain tissues of 9.5-month-old TD1+ / + and TD1+ / − mice (Scale bar = 2 mm); (fi) Quantitative neuropathological analysis of 9.5-month-old TD1+ / + and TD1+ / − mice: (f) Hippocampal atrophy (g) thickness of the piriform / entorhinal cortex, (h) volume of the posterolateral ventricle, (i) thickness of the dentate gyrus (DG) pyramidal neuron layer (n = 18 or 24); (j) Representative images of immunostaining of AT8 (phosphorylated tau), pTau217, and pTau181 in the hippocampus of TD1+ / + and TD1+ / - mice (n = 18 or 24); (k) Western blot analysis of AT8, pTau217, pTau181, and GAPDH (internal control) protein levels in hippocampal tissue; Figure 1 Middle (ln) is the quantitative analysis of phosphorylated tau deposition in the hippocampus of TD1+ / + and TD1+ / − mice: (l) percentage of AT8-positive area, (m) percentage of pTau217-positive area, (n) percentage of pTau181-positive area (n=5); Figure 1 Middle (oq) is quantitative analysis by qPCR and Western blot: (o) ATG1 mRNA expression (normalized to GAPDH), (p) pTau217 protein expression (normalized to GAPDH), (q) pTau181 protein expression (normalized to GAPDH) (n=5).

[0034] Figure 2 (a) Schematic diagram of the timeline of the experimental design for DGAT1 inhibitor treatment in PS19 transgenic mice; (b) representative images of brain tissue stained with acetic carmine from 9.5-month-old control (T-Con) and DGAT1 inhibitor-treated (T-iDGAT1) mice (scale bar = 4 mm); (cf) quantitative analysis results showing: (c) pathological changes in the hippocampus, (d) piriform / entorhinal cortex, (e) volume changes in the posterior lateral ventricle, and (f) comparison of the thickness of the pyramidal neuron layer in the dentate gyrus (DG).

[0035] Example 1

[0036] refer to Figure 1, DGAT1 deficiency significantly alleviates brain atrophy mediated by pathological tau protein. The steps of this example are as follows:

[0037] To investigate how DGAT1 deficiency affects tau pathology and neurodegeneration, we generated P301S Tau / DGAT1 mice. At 9.5 months of age, when mice exhibited significant tau pathology, neurodegeneration, and glial activation, we assessed hippocampal, entorhinal / pyriform cortex (EC / PC) volumes, ventricular volumes, and dentate gyrus (DG) thickness. Figure 1 ).

[0038] Experimental model: P301S tau transgenic mice (PS19 strain) were crossed with DGAT1 heterozygous (TD1+ / -) mice to obtain the P301S / DGAT1+ / - model.

[0039] Control group: P301S tau mice (DGAT1 wild type, TD1+ / +).

[0040] DGAT1+ / - mice were provided by CYAGEN. PS19 mice (B6; C3-Tg(Prnp-MAPT*P301S)PS19Vle / J; stock number #008169) were purchased from The Jackson Laboratory and backcrossed onto a C57BL / 6J background for more than 10 generations. Inbred strains were maintained by mating heterozygous transgenic males with C57BL / 6J females. Genomic DNA was extracted from tail biopsies, and genotypes were determined by PCR using the following primers:

[0041] DGAT1:F1:5'-GGTGCCTATAATAGGTTTCCT-3',

[0042] R1:5'-CCAAGAATAGTGTGCCATCTCCC-3,

[0043] F2:5'-TAATAGGTTTCCTGACCTGCTCC-3'

[0044] R2:5'-AATCTACCTGGGTATCTGTAGACCT-3'

[0045] PS19:Forward:5'-GGCATCTCAGCAATGTCTCC-3';

[0046] Reverse:5'-GGTATTAGCCTATGGGGGACA-3'

[0047] Wild-type(WT)control for PS19:Forward:5'-CAAATGTTGCTTGTCTGGTG-3'; Reverse:5'-GTCAGTCGAGTGCACAGTTT-3'.

[0048] Given that P301S transgenic male mice exhibit earlier and more pronounced brain dysfunction and tau phosphorylation compared to female mice, only male mice were evaluated in this study. Experimental animals were housed in a conventional barrier facility, five per cage, maintained on a 12-h light / dark cycle (22°C), with free access to water and a standard chow diet. Animal health monitoring strictly adhered to institutional veterinary protocols, and all experimental procedures were approved by the Ethics Committee of Chongqing Medical University.

[0049] Here’s how:

[0050] Nissl Staining

[0051] Brain sections from each group of mice were air-dried overnight at room temperature and then stained with cresyl violet for 15 minutes at room temperature. The sections were then dehydrated by immersion in graded ethanol (50%, 70%, and 95% ethanol three times, followed by 100% ethanol twice) for 1 minute each. The sections were then cleared in xylene (twice, 4 minutes each), and finally mounted with Cytoseal 60 mounting media (Thermo Fisher Scientific, Cat. No. 8310-16).

[0052] (2) Volume analysis and neuronal layer thickness measurement

[0053] The stained sections were imaged using a Zeiss laser confocal microscope (LSM980SCAN7CD7), and the outlines of each brain region were manually outlined for measurement: the volume of the hippocampus, posterolateral ventricle, and piriform / entorhinal cortex was calculated according to the formula: volume = (sum of the areas of each region) × 0.3 mm (slice spacing);

[0054] Thickness of the dentate gyrus (DG) neuron layer: Three slices were taken from each mouse, and vertical lines were drawn at two sites in each slice for measurement. The average value was taken as the final data.

[0055] Results: Compared with the control group, TD1+ / - mice showed significant increases in hippocampal volume and entorhinal / piriform cortex (EC / PC) volume ( Figure 1 Of particular note, the granule cell layer of the hippocampus of TD1+ / - mice showed significant thickening. In addition, a decrease in ventricular volume was observed in male TD1+ / - mice ( Figure 1), a morphological change often associated with progressive brain atrophy. Importantly, DGAT1 deficiency significantly alleviated the brain atrophy phenotype in PS19 mice. These results collectively suggest that DGAT1 plays a key regulatory role in the neurodegenerative process associated with tau pathology.

[0056] Example 2

[0057] refer to Figure 1 , disclosed on the basis of the above-mentioned embodiment 1.

[0058] Phosphorylated tau (pTau) accumulation is reduced in DGAT1 heterozygous mice. The steps of this example are as follows:

[0059] Significant tau pathology was observed in 9.5-month-old P301S tau transgenic mice, including increased insoluble tau species, accumulation of hyperphosphorylated tau, and extensive neurofibrillary tangles (NFTs). Notably, the accumulation of phosphorylated tau (pTau) in the hippocampus was significantly negatively correlated with the severity of neurodegeneration. To systematically evaluate the impact of DGAT1 deficiency on tauopathy, total tau and pTau levels were measured in the hippocampus.

[0060] Experimental model:

[0061] The same as above P301S / DGAT1+ / - mice, the control group was P301S / DGAT1+ / + mice.

[0062] The steps are as follows:

[0063] (1) Immunofluorescence staining

[0064] Sample preparation:

[0065] Permeabilization: Incubate sections with 0.1% Triton X-100 in PBS for 25 minutes at room temperature.

[0066] Blocking treatment: blocking with PBS solution containing 10% goat serum at 37°C for 60 minutes;

[0067] Primary antibody incubation:

[0068] Incubate overnight at 4°C with the following specific primary antibodies:

[0069] anti-p-tau(Ser202,Thr205)(Invitrogen,MN1020)

[0070] anti-pTau(Thr217)(zhao lab)

[0071] anti-pTau181 (Cell Signaling Technology, 12885S);

[0072] Secondary antibody treatment:

[0073] Wash with PBS three times (10 minutes each);

[0074] Incubate at 37°C for 1 hour:

[0075] Alexa Fluor 488 / 568 / 647-labeled secondary antibodies (Invitrogen, A-21202)

[0076] DAPI nuclear stain (Invitrogen, 62248, 0.5 mg / mL);

[0077] Mounting and imaging:

[0078] Wet mounting was performed using Vectashield mounting medium (Vector Laboratories, H-1000);

[0079] Images were collected using a confocal microscope (Olympus FluoView FV3000);

[0080] Image processing was performed using FV31S-SW imaging software (Olympus).

[0081] (2) Western Blot

[0082] Protein extraction:

[0083] After washing the cells three times with PBS, pre-chilled lysis buffer (Beyotime Biotechnology Research Institute) was added, supplemented with a protease and phosphatase inhibitor cocktail (Roche);

[0084] After lysis on ice for 30 min, the cells were centrifuged at 16,000 × g for 30 min at 4°C;

[0085] The supernatant was collected and the protein concentration was determined using a BCA protein quantification kit (Biyuntian).

[0086] Western blot detection:

[0087] Protein samples (1 μg / μL) were separated by 8% or 10% SDS-PAGE gel electrophoresis;

[0088] After transfer to nitrocellulose membrane, the membrane was blocked with TBST containing 7% skim milk;

[0089] Incubate with primary antibodies overnight at 4°C, including the following antibodies:

[0090] phosphorylated tau (Ser202 / Thr205, Invitrogen, MN1020);

[0091] total tau (Proteintech, 10274-1-AP);

[0092] phosphorylated tau (Thr181, Cell Signaling Technology, 12885S);

[0093] Phosphorylated tau (Thr217, Zhao lab);

[0094] GAPDH (Santa Cruz, sc-137179, internal reference);

[0095] After washing three times with TBST, the sections were incubated with HRP-labeled secondary antibody (Invitrogen, 31460100) at room temperature for 1 h;

[0096] After washing again, the membranes were developed using a chemiluminescent detection kit (PerkinElmer);

[0097] ImageJ software (NIH, USA) was used to quantitatively analyze the grayscale values ​​of the bands.

[0098] Results: Quantitative analysis of total tau and pTau levels in hippocampal tissue showed that pTau levels were significantly reduced in DGAT1-deficient mice. Immunohistochemical analysis using specific phosphorylated tau antibodies (AT8, pTau181, and pTau217) confirmed that TAM treatment significantly reduced the immunoreactivity of all three pTau markers in the hippocampus of TD1+ / - mice ( Figure 1 ).

[0099] These results consistently indicate that DGAT1 functional deficiency can effectively reduce the pathological phosphorylation level of tau protein in male transgenic mice.

[0100] Example 3

[0101] refer to Figure 2 , disclosed on the basis of the above-mentioned embodiment 1 and embodiment 2.

[0102] Pharmacological inhibition of DGAT1 alleviates tau pathology in PS19 mice. The steps of this example are as follows:

[0103] DGAT1 knockout mice exhibit significant metabolic phenotypes, including: lean body shape; resistance to diet-induced obesity and hepatic steatosis; enhanced systemic insulin / leptin sensitivity; and reduced tissue triglyceride accumulation.

[0104] Based on these findings, PF-04620110 (a pyrimidooxazolone compound with species-specific competitive inhibitory properties) was selected as a DGAT1 inhibitor to systematically evaluate its therapeutic potential in tauopathies. This will further clarify the translational medical value of DGAT1 regulation in tau pathology, establish cross-species pharmacodynamic relationships, and provide experimental evidence for clinical translation.

[0105] PS19 mice were orally treated with a DGAT1 inhibitor starting at 7 months of age and continued to receive treatment until 9.5 months of age, while pathological changes were monitored.

[0106] Here’s how:

[0107] The pharmacological intervention effect of the DGAT1 inhibitor PF-04620110 on tau pathology in PS19 transgenic mice was evaluated by oral administration. Specifically, 7-month-old PS19 mice were selected and administered 3 mg / kg (calculated by body weight) of PF-04620110 or 4 mg / kg of PF-06865571 once daily via stainless steel gavage needle for 10 weeks. The control group mice were treated with an equal volume of solvent. During the experiment, the weight changes and general health status of the mice were monitored daily to assess the safety and tolerability of the drug. This dosing regimen is designed to systematically study the intervention effect of DGAT1 inhibition on the progression of tau protein pathology and to establish a reliable preclinical pharmacodynamic evaluation system.

[0108] Experimental results: During the entire administration period, weight fluctuations and general health status were observed, and no significant differences were found between the treatment group and the control group in these parameters ( Figure 2 The mice remained in relatively good health. However, when analyzing the brain volumes of the different groups, it was found that the hippocampus and piriform cortex volumes of the treatment group were significantly increased compared to the control group ( Figure 2 The thickness of the neuronal layer in the dentate gyrus (DG) region was also significantly improved ( Figure 2 ), with partial reversal of ventricular enlargement.

[0109] Example 4

[0110] This disclosure is based on the above-mentioned embodiments 1 to 3.

[0111] The DGAT1 inhibitor is PF-04620110, which has a chemical structure of a pyridooxazolone derivative, a molecular formula of C20H18F3N3O3, and a molecular weight of 405.37. The DGAT1 inhibitor is PF-06865571, which has a chemical structure of a benzimidazole derivative, a molecular formula of C23H25F3N4O3, and a molecular weight of 462.47.

[0112] Example 5

[0113] Based on the above-mentioned Example 4, it is disclosed that DGAT1 inhibitors are used to treat pathological tau protein-related neurodegenerative diseases, and pathological tau protein-related neurodegenerative diseases include Pick disease (PiD), Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), familial tauopathy, etc.

[0114] Treated mice can be evaluated through pathological assessment, including changes in hippocampal and piriform cortex volume, phosphorylated tau protein levels, accumulation of glial lipid droplets in the brain, and microglial function.

[0115] The preferred embodiments of the present invention disclosed above are intended only to help illustrate the present invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the present invention to the specific embodiments described. Obviously, many modifications and variations are possible based on the contents of this specification. These embodiments are selected and described in detail in this specification to better explain the principles and practical applications of the present invention, thereby enabling those skilled in the art to better understand and utilize the present invention. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. Application of DGAT1-specific oral inhibitors in the treatment of tauopathy.

2. The use according to claim 1, characterized in that The DGAT1 inhibitor is PF-04620110 or PF-06865571.

3. The use according to claim 2, characterized in that The DGAT1 inhibitor is PF-04620110, which has a chemical structure of a pyridooxazolone derivative, a molecular formula of C20H18F3N3O3, and a molecular weight of 405.

37.

4. The use according to claim 2, characterized in that The DGAT1 inhibitor is PF-06865571, which has a chemical structure of a benzimidazole derivative, a molecular formula of C23H25F3N4O3, and a molecular weight of 462.

47.

5. Use of the DGAT1 inhibitor according to any one of claims 2 to 4 in the treatment of neurodegenerative diseases associated with pathological tau protein, characterized in that: The pathological tau protein-related neurodegenerative diseases include Pick's disease, Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial tauopathy.

6. The use according to claim 5, characterized in that A therapeutically effective amount of a DGAT1 inhibitor is administered to the patient.

7. The use according to claim 5, characterized in that: The application steps are as follows: PS19 mice were administered DGAT1 inhibitors, either PF-04620110 or PF-06865571, via stainless steel gavage. Oral administration daily for 10 weeks; Pathological evaluation was performed on PS19 mice after the end of drug administration.

8. The use according to claim 7, characterized in that: The pathological assessment included changes in the volume of the hippocampus and piriform cortex, levels of phosphorylated tau protein, accumulation of lipid droplets in brain glial cells, and function of microglia.

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