2-naphthalenethiol or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer's disease

Abstract

The present application relates to the use of 2-naphthalenethiol or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Alzheimer's disease. The present application first proves that 2-naphthalenethiol can significantly enhance autophagy activity in model animals on one hand, efficiently promote the clearance of aggregated beta-amyloid protein (Aβ), and reduce the damage of the characteristic pathological protein deposition of Alzheimer's disease to neurons from the root, on the other hand, the compound can effectively improve the immune response. The above-mentioned autophagy activation, lysosome activity enhancement and immune level regulation pathway can produce synergies, jointly alleviate the neurodegeneration process related to Alzheimer's disease, achieve the protection of nerve degeneration, and delay the pathological progression of the disease.

Description

Technical Field

[0001] This invention relates to the field of new drug technology, specifically to the use of 2-naphthiol or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating Alzheimer's disease. Background Technology

[0002] Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease and the most common cause of dementia. Its typical pathological features include senile plaques formed by the deposition of β-amyloid (Aβ) protein in the brain and neurofibrillary tangles formed by hyperphosphorylated tau protein. Early symptoms include memory loss, followed by language impairment, behavioral changes, and a decline in daily living abilities.

[0003] 2-Naphthalenethiol, also known as 2-mercaptonaphthalene, is an organic compound with the chemical formula C64-22-22-23-2 ... 10 H8S, with a molecular weight of 160.24 and CAS number 91-60-1, is a white to cream-colored powder with a melting point of 79-81℃, a boiling point of 286℃, and a density of 1.22 g / mL. It is slightly soluble in water and readily soluble in ethanol, ether, and petroleum ether. Its structural formula is shown below; it is a thiol compound. Thiol compounds are not entirely new structures in medicinal chemistry, and some are known to have applications in the treatment of neurological diseases. However, the potential of 2-naphthylthiol in the treatment of Alzheimer's disease and its specific mechanism of action have not been previously reported.

[0004] Summary of the Invention

[0005] (a) Technical problems to be solved To overcome the shortcomings and deficiencies of existing technologies, this invention provides the use of 2-naphthylthiol or a pharmaceutically acceptable salt thereof in the preparation of drugs for the treatment or prevention of Alzheimer's disease. This compound can act simultaneously on two core pathways: on the one hand, it enhances autophagy and lysosomal activity in model animals to clear aggregated β-amyloid protein; on the other hand, it enhances the immune response. These two actions synergistically alleviate Alzheimer's-related neurodegeneration. This invention not only provides novel drug candidate molecular entities but also lays a solid technological foundation for the development of Alzheimer's disease drugs.

[0006] (II) Technical Solution This invention provides the use of 2-naphthiol or a pharmaceutically acceptable salt or solvate thereof in the preparation of medicaments for the treatment or prevention of Alzheimer's disease.

[0007] Furthermore, 2-naphthiol or a pharmaceutically acceptable salt thereof exerts a synergistic effect in treating or alleviating Alzheimer's disease-related neurodegeneration by enhancing autophagy and lysosomal activity in animals and promoting the clearance of aggregated β-amyloid protein.

[0008] Furthermore, 2-naphthiol or a pharmaceutically acceptable salt thereof exerts a therapeutic effect by enhancing the immune response.

[0009] Furthermore, 2-naphthiol or its pharmaceutically acceptable salts exert therapeutic effects on Alzheimer's disease by synergistically enhancing autophagy and lysosomal activity in animals to promote the clearance of aggregated β-amyloid protein pathways, as well as enhancing immune responses.

[0010] Furthermore, the Alzheimer's disease drug uses 2-naphthylthiol or a pharmaceutically acceptable salt thereof as its sole active ingredient.

[0011] Furthermore, the Alzheimer's disease drug comprises a combination of two or more pharmacologically active ingredients, wherein at least one pharmacologically active ingredient is 2-naphthiol or a pharmaceutically acceptable salt thereof.

[0012] Furthermore, the Alzheimer's disease medication contains a pharmacologically active ingredient selected from the following: cholinesterase inhibitors, NMDA receptor antagonists, antidepressants, antipsychotics, and anxiolytics.

[0013] Furthermore, the Alzheimer's disease drug also contains pharmaceutically acceptable excipients and / or delivery carriers.

[0014] Furthermore, the dosage form of the drug is an oral preparation, an injectable preparation, a transdermal absorption preparation, or a mucosal delivery preparation.

[0015] Furthermore, pharmaceutically acceptable salts of 2-naphthylthiol are pharmaceutical salts formed by 2-naphthylthiol with inorganic or organic acids.

[0016] Further, the inorganic acid is at least one selected from sulfuric acid, hydrochloric acid, azironic acid and phosphoric acid, and the organic acid is at least one selected from acetic acid, oxalic acid, citric acid, gluconic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, lactic acid, succinic acid, tartaric acid and maleic acid.

[0017] Furthermore, the pharmaceutically acceptable salt of the 2-naphthiol also contains a solvent compound of the salt, such as a hydrate or alcohol.

[0018] Furthermore, the drug is a pharmaceutical complex consisting of 2-naphthiol or a pharmaceutically acceptable salt thereof as the active ingredient and a pharmaceutical excipient.

[0019] Furthermore, the drug can be metabolized in vivo to release 2-naphthiol or a pharmaceutically acceptable salt thereof.

[0020] Another aspect of the present invention provides a pharmaceutical composition for the prevention and / or treatment of Alzheimer's disease, comprising: 2-naphthiol or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, and pharmaceutical excipients and / or delivery carriers.

[0021] Furthermore, the pharmaceutical composition also contains additional active ingredients for the prevention or treatment of Alzheimer's disease, preferably selected from the following active ingredients: cholinesterase inhibitors, NMDA receptor antagonists, antidepressants, antipsychotics, and anxiolytics.

[0022] Furthermore, the pharmaceutical composition is in solid, liquid or semi-solid form, preferably an oral formulation, an injectable formulation, a transdermal absorption formulation or a mucosal delivery formulation.

[0023] Furthermore, pharmaceutically acceptable salts of 2-naphthylthiol are pharmaceutical salts formed by 2-naphthylthiol with inorganic or organic acids.

[0024] Further, the inorganic acid is at least one selected from sulfuric acid, hydrochloric acid, azironic acid and phosphoric acid, and the organic acid is at least one selected from acetic acid, oxalic acid, citric acid, gluconic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, lactic acid, succinic acid, tartaric acid and maleic acid.

[0025] Furthermore, the pharmaceutically acceptable salt of the 2-naphthiol also contains a solvent compound of the salt, such as a hydrate or alcohol.

[0026] In one specific embodiment, the pharmaceutical composition is a tablet, capsule, granule, powder, solution, injection, infusion, oral preparation, drops, inhaler, suppository, or patch.

[0027] Any therapeutic application described in this invention can be applied to any subject requiring the therapy, including, for example, mammals such as humans, dogs, cats, cattle, horses, rabbits, monkeys, pigs, sheep, goats, or rodents such as mice or rats.

[0028] Those skilled in the art can, for example, use Remington: The Science and Practice of Pharmacy The teachings of the standard textbook, 23rd edition (Academic Press, 2021), and the ease with which the reagents of the present invention can be formulated into pharmaceutical compositions or pharmaceutical preparations or kits suitable for administration to subjects such as humans, taking into account the chosen route of delivery.

[0029] The reagents of the present invention or their pharmaceutical salts can be used as pharmaceutical agents, for example, in the form of pharmaceutical compositions. These pharmaceutical compositions can be administered orally, for example, in the form of tablets, coated tablets, sugar lozenges, hard and soft gelatin capsules, solutions, emulsions, or suspensions. However, administration can also be performed, for example, rectally in the form of suppositories, or parenterally in the form of injections.

[0030] The reagents of the present invention (2-naphthylthiol or its pharmaceutical salts or solvates) can be processed together with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical formulations. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as such carriers for tablets, coated tablets, syrups, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, depending on the nature of the active substance, a carrier is generally not required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, glucose, etc. Excipients, such as alcohols, polyols, glycerol, vegetable oils, etc., can be used in the aqueous solutions of the water-soluble salts of the reagents of the present invention, but are generally not essential. Suitable carriers for suppositories include, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0031] In addition, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts that alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances of therapeutic value.

[0032] Dosage can vary within a wide range and will, of course, be tailored to individual needs in each specific situation. Typically, the effective dose for oral or parenteral administration is 0.01–50 mg / kg / day, with a preferred dose of 0.1–30 mg / kg / day, e.g., 20 mg / kg / day, for all the indicated uses. Dosage can be administered continuously for 2–28 days (e.g., days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28).

[0033] (III) Beneficial Effects 1. This invention uses the Caenorhabditis elegans AD model to demonstrate that 2-naphthiol can significantly enhance autophagy and lysosomal activity in the model animals, thereby efficiently promoting the clearance of aggregated β-amyloid protein, fundamentally reducing the damage to neurons caused by the deposition of characteristic pathological proteins in Alzheimer's disease, and blocking the neurotoxic pathway mediated by pathological proteins.

[0034] 2. This compound can effectively enhance the immune response and reduce the risk of nerve cell apoptosis caused by abnormal immune system function.

[0035] 3. The two pathways mentioned above, namely autophagy activation and enhanced lysosomal activity, and enhanced immune response regulation, can have a synergistic effect, jointly alleviating the neurodegenerative process associated with Alzheimer's disease, reducing β-amyloid protein accumulation, and delaying the pathological progression of the disease.

[0036] 4. This invention provides a novel candidate molecular entity for the treatment of Alzheimer's disease, fills the technological gap in existing therapeutic drugs on dual-pathway synergistic intervention targets, and provides key technical support and new research directions for the development of innovative anti-Alzheimer's drugs.

[0037] In summary, 2-naphthiosulfate not only provides a novel candidate molecular entity for the treatment of Alzheimer's disease, but also further confirms the great potential of simultaneously targeting autophagy and immune homeostasis as a multi-target therapeutic strategy, laying a solid theoretical foundation and experimental evidence for the development of next-generation neuroprotective agents. Attached Figure Description

[0038] Figure 1 Experimental results for 2-naphthiosulfate to alleviate the phenotype of the AD nematode model.

[0039] Figure 2 The results show that 2-naphthiosulfate inhibits the aggregation of β-amyloid protein in an AD model nematode.

[0040] Figure 3 The experimental results of 2-naphthiosulfate in alleviating cognitive impairment in Alternaria radiata.

[0041] Figure 4 Experimental results showing that 2-naphthiool enhances autophagy in the head of *A. sarcodactylus*.

[0042] Figure 5 Experimental results on the enhancement of lysosomal activity by 2-naphthiol.

[0043] Figure 6 The experimental results show that 2-naphthiol enhances the immune response. Detailed Implementation

[0044] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0045] Unless otherwise indicated, the terms used herein have their general technical meanings as understood by those skilled in the art.

[0046] In this invention, the singular articles “a” and “the” cover a plurality of indicators unless the context clearly indicates otherwise. All references cited herein are incorporated herein by reference in their entirety.

[0047] The use of "comprising" or "including" in this invention is an open-ended description that includes all specified components or steps described, as well as other specified components or steps that do not materially affect the description.

[0048] The term "and / or" as used in this invention encompasses all combinations of items connected by the term, and should be considered as if each combination had been individually listed herein. For example, "A and / or B" includes "A", "A and B", and "B". As another example, "A, B and / or C" includes "A", "B", "C", "A and B", "A and C", "B and C", and "A and B and C".

[0049] The present invention is further illustrated in the following embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified, the reagents, materials, etc., used in the embodiments are commercially available. Unless otherwise specified, the methods used in the embodiments of this application are conventional methods in the prior art.

[0050] Caenorhabditis elegans has become a classic model for studying protein homeostasis, immune function, and the mechanisms of neurodegenerative diseases, as well as for drug screening, due to its simple nervous system structure, short life cycle, clear genetic background, and ease of gene manipulation. In particular, transgenic nematodes expressing human β-amyloid protein can accurately mimic the core pathological features of AD, such as β-amyloid protein aggregation, learning and memory disorders, and motor impairments, providing an efficient platform for rapid evaluation of the efficacy of candidate compounds at the whole animal level.

[0051] Example 1 In this embodiment, 2-naphthylthiol (CAS: 91-60-1; Inokai) was diluted to a concentration of 20 mM with ethanol and stored at -20°C. Then, 2-naphthylthiol was diluted to a concentration of 1 mM with OP50 (Escherichia coli, purchased from the Nematode Genetic Center, https: / / cgc.umn.edu / strain / search) bacterial culture for use in subsequent experimental procedures.

[0052] OP50 bacterial suspension refers to a cultured suspension of the Escherichia coli OP50 strain, used for laboratory feeding of the model organism *C. elegans*. *E. coli* OP50 is a commonly used uracil auxotrophic strain with a slow growth rate, forming a thin, uniform bacterial mat on nematode culture plates, facilitating observation of nematode growth, development, and behavior. In this experiment, 20 mM of the stock solution of 2-naphthiolol was diluted into 1 mM of the OP50 bacterial suspension. *C. elegans* was then fed this compound to the nematodes to study its biological effects.

[0053] Example 2 This example demonstrates that a concentration of 1 mM 2-naphthylthiol can alleviate the phenotype of Alzheimer's disease in a nematode model. The experimental method involved selecting four L4-stage AD model nematodes (Alzheimer's disease model nematodes). Two strains of these nematodes were used: the first strain was P... unc-54 ::A-beta(1-42)(GMC101) (abbreviated as GMC101 strain, model see McColl G, Roberts BR, Pukala TL, et al. Utility of an improved model of amyloid-beta (Aβ)) 1-42 )toxicity in Caenorhabditis elegans for drug screening for Alzheimer'sdisease. Mol Neurodegener. 2012;7:57. Published 2012 Nov 21. doi:10.1186 / 1750-1326-7-57); the second one is: P myo-3 ::GFP::A-Beta (3-42)(CL2331) (abbreviated as CL2331 strain, model see Link CD, Fonte V, Roberts CM, Hiester B, Silverman MA, Stein GH. The beta amyloid peptide can act as a modular aggregation domain. Neurobiol Dis.2008;32(3):420-425. doi:10.1016 / j.nbd.2008.08.003). The first strain is constructed by expressing A-beta 1-42 The plasmid was then microinjected into nematodes and screened. The second strain was obtained by constructing a strain expressing A-beta. 3-42The plasmids were then microinjected into nematodes and screened. GMC101 was inoculated onto a medium plate coated with 1 mM 2-naphthylthiol. After culturing for 3-4 days, L4 progeny nematodes were transferred to a new medium plate with the same concentration of 2-naphthylthiol and treated at 25°C for 24 hours. The number of paralyzed nematodes was counted on day 1 (D1). CL2331 was inoculated onto a medium plate coated with 1 mM 2-naphthylthiol. After culturing for 7 days, L4 progeny nematodes (CL2331 survives at 15°C and grows slowly) were selected and transferred to a new medium plate with the same concentration of 2-naphthylthiol and treated at 25°C for 48 hours. The number of Aβ aggregation sites in the nematodes was counted on day 2 (D2). The relevant experimental results are shown in […]. Figure 1 , Figure 2 .

[0054] in, Figure 1 This shows the experimental results of alleviating the paralysis phenotype in the AD model nematodes with concentrations of 10 μM and 1 mM 2-naphthylthiol. The figure shows a statistical chart of the number of paralyzed GMC101 nematodes after feeding with Ethanol + OP50 and 10 μM and 1 mM 2-naphthylthiol. Figure 1 As shown, the paralysis rate of GMC101 nematodes fed the control group (Ethanol + OP50) was higher than that of nematodes fed 10 μM and 1 mM 2-naphthylthiol. Furthermore, **p < 0.01 (statistically significant), indicating that this compound has a clear and reliable effect on alleviating the paralysis phenotype in the AD model. These results demonstrate that 1 mM 2-naphthylthiol can effectively alleviate the paralysis phenotype in the AD model. Subsequent experiments will use this concentration.

[0055] exist Figure 2 The experimental results further verified that the intervention effect of 1 mM 2-naphthiolol on the β-amyloid aggregation strain of the AD model nematode further verified its role in resisting Alzheimer's disease-related pathological damage. Figure 2 This figure shows the experimental results of inhibiting the aggregation of β-amyloid protein masses in the AD model nematode using 1 mM 2-naphthylthiol. The figure includes a diagram and statistical analysis of the protein aggregates in the head of the β-amyloid nematode after feeding with Ethanol + OP50 and 1 mM 2-naphthylthiol. White arrows indicate the protein aggregates. Scale bar = 20 μm, p < 0.0001. Figure 2 The fluorescence imaging results of (A) show that the control group (fed Ethanol + OP50) of β-amyloid nematodes had a large number of β-amyloid protein aggregates in their heads, indicated by white arrows. However, after treatment with 1 mM 2-naphthiol (abbreviated as 2-Naph), the number of protein aggregates in the heads was significantly reduced and the distribution density was significantly decreased; the corresponding statistical data ( Figure 2(B) also showed that the number of β-amyloid aggregates in the 2-Naph group was much lower than that in the control group, and the result of ****p<0.0001 suggested that this difference was highly statistically significant.

[0056] The above experimental results and Figure 1 A functional association was established between 2-naphthylthiol and the paralysis phenotype in the Alzheimer's disease (AD) model: 2-naphthylthiol not only alleviates paralysis in the AD model but also directly inhibits the abnormal aggregation of β-amyloid protein, a key pathogenic factor in AD, which is one of the core pathological processes inducing AD. Combined with the compound's mechanism of action of "enhancing autophagy activity to clear aggregated proteins," the results clearly demonstrate that 2-naphthylthiol can alleviate pathological damage in the *Nematodea* nematode model of Alzheimer's disease by reducing pathogenic protein aggregation and mitigating protein toxicity. These experimental results suggest that 2-naphthylthiol has the potential to be a candidate molecule for Alzheimer's disease treatment.

[0057] Example 3 This embodiment further utilizes GRU101 (P) myo-2 ::YFP), GRU102 (P myo-2 ::YFP + P unc-119 ::Abeta1-42) nematode model (GRU101 model see Fong S, Teo E, Ng LF, et al. Energy crisisprecedes global metabolic failure in a novel Caenorhabditis elegans AlzheimerDisease model. Sci Rep. 2016;6:33781. Published 2016 Sep 22. doi:10.1038 / srep33781; For the GRU102 model, see Fong S, Teo E, Ng LF, et al. Energy crisis precedes global metabolic failure in a novel Caenorhabditis elegans Alzheimer Disease model. Sci Rep. 2016;6:33781. Published 2016 Sep 22. (doi:10.1038 / srep33781) verified the alleviating effect of 2-naphthiosulfate on cognitive learning and memory impairment in Alzheimer's disease nematodes.

[0058] The experimental method was as follows: Control and model nematodes GRU101 and GRU102 were inoculated onto plates coated with the solvent control Ethanol + OP50 and 1 mM 2-naphthylthiol, respectively. After 3 days, the L4 stage progeny nematodes were transferred to new plates coated with Ethanol + OP50 and 1 mM 2-naphthylthiol. The number of times the nematodes touched and attempted to escape was measured on day 1. Results are shown below. Figure 3 . Figure 3 The graph shows the number of times GRU101 and GRU102 nematodes were touched and escaped after being fed Ethanol+OP50 and 1mM 2-naphthylthiol. ***p<0.001, ****p<0.0001. This experiment demonstrates that 1mM 2-naphthylthiol can effectively alleviate learning and memory impairment in Alzheimer's disease.

[0059] Specifically, from Figure 3 Statistical results showed that GRU102 in the Ethanol+OP50 group exhibited significantly more touch avoidance than GRU101 in the Ethanol+OP50 group, and the result of p<0.001 indicated that this difference was highly statistically significant. This result reflects learning and memory impairment in GRU102. GRU102 in the 1 mM 2-naphthylthiol group exhibited significantly fewer touch avoidances than GRU102 in the Ethanol+OP50 group, and the result of p<0.0001 indicated that this difference was highly statistically significant. This result reflects that a concentration of 1 mM 2-naphthylthiol can effectively alleviate learning and memory impairment in Alzheimer's disease.

[0060] Example 4 This embodiment further verified the regulatory role of 2-naphthiol on autophagy activity using a PHA-4::GFP nematode model (PHA-4 is a transcriptional regulator of autophagy, and GFP is a fluorescent marker) (the PHA-4::GFP nematode model was purchased from the Caenorhabditis Genetics Center (CGC)).

[0061] The experimental method was as follows: Autophagy-labeled nematodes PHA-4::GFP were inoculated onto a plate coated with 1 mM 2-naphthylthiol. Three days later, L4-stage progeny nematodes were transferred to a new plate coated with 1 mM 2-naphthylthiol. On day 1, the number of nuclei in the nematode head indicating the level of autophagy was measured. Results are shown below. Figure 3 . Figure 3 A diagram and statistical analysis of positive nuclei in the head of PHA-4::GFP nematodes after feeding with Ethanol+OP50 and 1 mM 2-naphthylthiol. Scale bar = 20 μm, ****p < 0.0001. This figure demonstrates that 1 mM 2-naphthylthiol enhances autophagy.

[0062] Specifically, from Figure 4 The fluorescence images showed that the number of positive nuclei in the heads of nematodes in the control group (fed Ethanol + OP50) increased significantly after treatment with 1 mM 2-naphthiool (2-Naph). Figure 4 Further statistical results showed that the number of positive nuclei in the head of the 2-Naph group was significantly higher than that in the control group, and the result of p < 0.0001 indicated that this difference was highly statistically significant. This result directly supports the core mechanism of action of 2-naphthiol, namely, enhancing autophagy activity: activation of the autophagy pathway can accelerate the degradation of toxic protein substrates, including abnormally aggregated β-amyloid protein, and the increase in positive nuclei of PHA-4 in this experiment is a manifestation of enhanced autophagy function. Figure 2 The reduction in β-amyloid protein aggregation further clarifies that 2-naphthiol exerts its protective effect against Alzheimer's disease model nematodes through the pathway of "enhanced autophagy → clearance of pathogenic proteins," which echoes the hypothesis of "synergistic interaction between enhanced autophagy and enhanced immune function."

[0063] Example 5 This embodiment further utilizes P hsp-16.2 The ::NUC-1::pHTomato nematode model (see Sun Y, Li M, Zhao D, Li X, Yang C, Wang X. Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans. Elife. 2020;9:e55745. Published 2020 Jun 2. doi:10.7554 / eLife.55745) (using pH value to reflect acidity and further reflect lysosomal activity) verified the regulatory role of 2-naphthiol on lysosomal activity.

[0064] The experimental method was as follows: nematodes labeled with pH values ​​(P) were... hsp-16.2 ::NUC-1::pHTomato was inoculated onto a plate coated with 1 mM 2-naphthylthiol. After 3 days, the L4 stage progeny nematodes were transferred to a new plate coated with 1 mM 2-naphthylthiol. After treatment at 33°C for 30 min, the plate was placed at 20°C on day 1, and the average fluorescence intensity of individual lysosomes of the nematodes was measured. Results are shown below. Figure 5 . Figure 5 After feeding Ethanol + OP50 and 1mM 2-naphthiolol, P hsp-16.2A graphical representation and statistical analysis of the average fluorescence intensity of a single lysosome in *Nematodea 'NUC-1::pHTomato'*, scale bar = 20 μm, *p < 0.05. This figure demonstrates the effect of 1 mM 2-naphthiolol in enhancing lysosomal activity.

[0065] Specifically, from Figure 5 As seen in the fluorescence images, the average fluorescence intensity of individual lysosomes in the control group (fed Ethanol + OP50) was brighter; after treatment with 1 mM 2-naphthiol (2-Naph), the average fluorescence intensity of individual lysosomes decreased significantly. Figure 5 Further statistical results showed that the average fluorescence intensity of individual lysosomes in the 2-Naph group was significantly lower than that in the control group, and *p<0.05 indicated that this difference was highly statistically significant. This result directly supports the core mechanism of action of 2-naphthiolol, namely, enhancing autophagic lysosomal activity. Figure 2 The reduction in β-amyloid aggregation, Figure 4 Elevated autophagy levels further clarify that 2-naphthiol exerts its protective effect against Alzheimer's disease model nematodes through the pathway of "enhancing autophagy, enhancing lysosomal activity → clearing pathogenic proteins," which echoes the hypothesis of "synergistic interaction between the dual pathways of enhancing autophagy and lysosomes and enhancing immune function."

[0066] Example 6 This example demonstrates that 1 mM 2-naphthiol can enhance the immune response.

[0067] The experimental method was as follows: nematodes labeled with immune levels (P) were... ATF-7 ::ATF-7::TY1::GFP (model see Sarov M, Schneider S, Pozniakovski A, et al. A recombineering pipeline for functional genomics applied to Caenorhabditis elegans. Nat Methods. 2006;3(10):839-844. doi:10.1038 / nmeth933) was inoculated onto a plate coated with 1 mM 2-naphthylthiol. Three days later, the L4 stage progeny nematodes were transferred to a new plate coated with 1 mM 2-naphthylthiol. On the first day, the fluorescence intensity of the positive nuclei from the oviposition stage to the tail was measured. Results are shown in […]. Figure 6 After feeding Ethanol + OP50 and 1mM 2-naphthiolol, P ATF-7 Display image and fluorescence statistics of ::ATF-7::TY1::GFP nematodes, scale bar = 20μm.

[0068] Figure 6 The fluorescence spectrum showed that, through P ATF-7 The experimental results of the ::ATF-7::TY1::GFP nematode model (ATF-7 is a transcriptional regulator of the immune response) clearly show that the control group (fed Ethanol + OP50) nematodes exhibited weak fluorescence signals, while after treatment with 1 mM 2-naphthylthiol (2-Naph), P... ATF-7 The mean fluorescence intensity of the nuclei of ::ATF-7::TY1::GFP nematodes was significantly increased, and Figure 6 The statistical result of p<0.0001 indicates that the difference is statistically significant. This result directly proves that 2-naphthiosulfate can effectively enhance immune levels.

[0069] The results from Examples 2-4 demonstrate that 2-naphthylthiol enhances autophagy and reduces β-amyloid protein aggregation, thus revealing its complete mechanism of action. This compound works by enhancing both immune function and autophagy to clear pathogenic proteins; the synergistic effect of these two pathways is the key mechanism by which it alleviates neurodegeneration in the Alzheimer's disease (AD) model nematode, providing comprehensive mechanistic and experimental support for its potential as a candidate molecule for AD treatment.

[0070] Immune dysfunction is one of the core pathological aspects of Alzheimer's disease (AD). The experiments described above demonstrate that 2-naphthiol effectively activates the immune system, which is one of the key mechanisms by which it exerts its protective effect against AD.

[0071] Based on the model system of transgenic Caenorhabditis elegans expressing human β-amyloid protein, this invention systematically verifies the AD protective effect of 2-naphthiol: this compound exhibits significant neuroprotective and protein aggregation inhibition effects in various AD nematode models, fully demonstrating its good application potential in the field of Alzheimer's disease treatment.

[0072] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features. These modifications or substitutions, or combinations of technical features in the above embodiments that do not conflict with each other, can be made in accordance with the manner described in the embodiments. These modifications, substitutions or combinations do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

Use of 1,2-naphthiol or a pharmaceutically acceptable salt or solvate thereof in the preparation of medicines for the treatment or prevention of Alzheimer's disease.

2. The use according to claim 1, wherein the 2-naphthiol or a pharmaceutically acceptable salt thereof enhances autophagy activity in vivo and / or promotes the clearance of aggregated β-amyloid protein.

3. The use according to claim 1, wherein 2-naphthiol or a pharmaceutically acceptable salt thereof synergistically enhances the pathways of autophagy activity and promotes the clearance of aggregated β-amyloid protein in vivo.

4. The use according to any one of claims 1 to 3, wherein the Alzheimer's disease drug is composed solely of 2-naphthiol or a pharmaceutically acceptable salt thereof.

5. The use according to any one of claims 1 to 3, wherein the Alzheimer's disease drug comprises a combination of two or more pharmacologically active ingredients, wherein at least one pharmacologically active ingredient is 2-naphthiol or a pharmaceutically acceptable salt thereof.

6. The use according to claim 5, wherein the Alzheimer's disease drug comprises a pharmacologically active ingredient selected from: cholinesterase inhibitors, NMDA receptor antagonists, antidepressants, antipsychotics, and anxiolytics.

7. The use according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt of said 2-naphthylthiol is a pharmaceutically acceptable salt formed by 2-naphthylthiol with an inorganic or organic acid, preferably the inorganic acid being at least one selected from sulfuric acid, hydrochloric acid, azironic acid and phosphoric acid, and the organic acid being at least one selected from acetic acid, oxalic acid, citric acid, gluconic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, lactic acid, succinic acid, tartaric acid and maleic acid.

8. A pharmaceutical composition for the prevention and / or treatment of Alzheimer's disease, comprising: 2-naphthiol or a pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutical excipients and / or delivery carriers.

9. The pharmaceutical composition of claim 8, further comprising an additional active ingredient for the prevention or treatment of Alzheimer's disease, preferably selected from the following active ingredients: cholinesterase inhibitors, NMDA receptor antagonists, antidepressants, antipsychotics, and anxiolytics.

10. The pharmaceutical composition according to claim 8 or 9, wherein it is in solid, liquid or semi-solid form, preferably an oral formulation, an injectable formulation, a transdermal absorption formulation or a mucosal delivery formulation.

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