Application of GPE analogue in preparation of medicine for preventing and / or treating Alzheimer disease

Abstract

The invention relates to an application of a GPE analogue or a pharmaceutically acceptable derivative thereof in preparation of a medicine for preventing and / or treating Alzheimer's disease (AD). Experiments prove that the GPE analogue can significantly improve cognitive impairment of mice with AD diseases and significantly improve cognitive competence of the mice for the first time; furthermore, the inventor researches the pathological mechanism of the GPE analogue to find that the GPE analogue can obviously reduce beta-amyloid protein deposition in cerebral cortex and hippocampus, so that the toxicity of the GPE analogue to nerve cells is obviously reduced, and therefore, the GPE analogue can be used for preventing, relieving, improving or treating the AD disease or delaying the progress of the AD disease, and has a good application prospect. The compound is expected to become a candidate therapeutic drug for Alzheimer's disease, and has great clinical application prospect and value.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to use of a GPE analog or a pharmaceutically acceptable derivative thereof in preparing a drug for preventing and / or treating Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD) is the most common progressive neurodegenerative disease, accounting for about 50%-70% of senile dementia cases, characterized by neuronal loss, synaptic dysfunction and progressive cognitive decline. Its pathological hallmarks include senile plaques (SP) formed by the extracellular deposition of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) formed by the intracellular aggregation of hyperphosphorylated tau protein. The pathogenesis of AD is complex, involving the interaction of multiple factors such as genetics, metabolic abnormalities, neurotransmitter system dysfunction, blood-brain barrier damage and DNA repair disorders. There is currently no cure, and clinical treatment is mainly aimed at delaying disease progression and alleviating symptoms.

[0003] At present, AD treatment is mainly symptomatic treatment. Current AD treatment drugs are mainly divided into the following categories:

[0004] (1) Cholinesterase inhibitors (ChEIs): improve cognitive function by inhibiting acetylcholine degradation, but can only temporarily relieve symptoms;

[0005] (2) Glutamate receptor inhibitors (such as memantine): regulate glutamatergic neurotransmission but have no reversal effect on the course of the disease;

[0006] (3) Drugs that improve cerebral circulation and protect neurons (such as nimodipine): limited efficacy and lack of specificity;

[0007] (4) Antioxidants and calcium channel blockers: Most of them are in the experimental stage and there is insufficient clinical evidence.

[0008] The main benefits of these drugs are to delay further deterioration of cognitive function and alleviate clinical symptoms, but they do not change the course of disease development.

[0009] In recent years, monoclonal antibody drugs (such as lencanezumab) targeting the core targets of AD pathology (such as Aβ and tau protein) have been used to remove Aβ plaques through intravenous injection, becoming a breakthrough in causal treatment. However, such drugs have significant defects, such as single target: only intervening in a certain pathological link of Aβ or tau, unable to reverse the irreversible neuronal damage that has occurred; narrow treatment window: need to be administered during the window period between abnormal Aβ aggregation and cognitive impairment, clinical applicability is limited; there are safety risks: may cause cerebrovascular inflammation, edema or bleeding and other serious side effects.

[0010] Insulin-like growth factor 1 (IGF-1) is a naturally occurring peptide and a potent neurotrophic factor in the central nervous system (CNS), playing an important role in the growth of the CNS and the regulation of mature neuronal and glial functions. However, currently available IGF-1 therapeutics are not ideal. Recombinant human IGF-1 is usually administered subcutaneously or intravenously, but this route of administration results in increased peripheral levels, which can bring significant cancer risks and may shorten lifespan. Supplements containing IGF-1 are available on the market, but IGF-1 in pill form may break down in the intestine before reaching the blood. Therefore, the research focus on this target has gradually shifted to its cleavage products with reduced carcinogenicity and / or better bioavailability.

[0011] In brain tissue, IGF-1 is cleaved by acidic proteases into the N-terminal tripeptide motif glycine-L-proline-L-glutamate (GPE). Compared with IGF-1, GPE can more effectively stimulate the release of acetylcholine from rat brain tissue by several orders of magnitude and has a dose-dependent neuroprotective effect, but it has the problem of a short half-life in the blood and brain. In order to further improve its performance, a series of new derivatives have been continuously synthesized and developed, for example, β-methylproline is substituted for proline to provide GPE analogs with better performance, for example, glycyl-L-2-methylprolyl-L-glutamate (GLXC-15737) is one of them, and its structural formula is shown in Formula I:

[0012]

[0013] The GPE analogue shown in the above formula I has a prolonged half-life in the blood and brain and has been approved for the treatment of Rett syndrome in children, but there is currently no literature reporting that it can be used to prevent and treat Alzheimer's disease. Summary of the invention

[0014] Purpose of the Invention

[0015] The object of the present invention is to provide the use of the GPE analogue shown in Formula I or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for preventing and / or treating Alzheimer's disease.

[0016] The present invention discovers for the first time that the GPE analogues shown in Formula I or their pharmaceutically acceptable derivatives can significantly improve cognitive dysfunction in AD and delay the course of the disease, and because of their long half-life in the blood and brain, they provide a new and effective treatment option for AD.

[0017] Solution

[0018] To achieve the above object, the present invention adopts the following technical solution:

[0019] In a first aspect, the present invention provides the use of a GPE analogue or a pharmaceutically acceptable derivative thereof as shown in Formula I in the preparation of a medicament for preventing and / or treating Alzheimer's disease:

[0020]

[0021] In a specific embodiment, the pharmaceutically acceptable derivative of the GPE analog is a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0022] Preferably, the pharmaceutically acceptable derivative of the GPE analog is a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof. The prodrug is a drug that can be converted into the GPE analog of Formula I in vivo.

[0023] Possibly, the salt of the GPE analog is a salt type thereof selected from the group consisting of hydrochloride, phosphate, sulfate, fumarate, succinate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, lactate, malate, maleate, glutarate, oxalate or succinyl hemiamine salt.

[0024] In the above use, the treatment of Alzheimer's disease includes one or more of the following:

[0025] (1) Slow down the progression of Alzheimer's disease;

[0026] (2) Improve symptoms caused by Alzheimer's disease;

[0027] Preferably, the treatment of Alzheimer's disease is to alleviate cognitive dysfunction caused by Alzheimer's disease.

[0028] In the above use, the prevention and / or treatment of Alzheimer's disease is preferably achieved through the following mechanism: reducing the deposition of β-amyloid protein.

[0029] In the above-mentioned use, preferably, the medicine comprises a preventive and / or therapeutically effective amount of the GPE analog or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0030] Further preferably, the preventive effective amount of the GPE analog or its pharmaceutically acceptable derivative is 40-60 mg / kg body weight, preferably 50 mg / kg body weight, and the therapeutic effective amount is 80-120 mg / kg body weight, preferably 100 mg / kg body weight.

[0031] Preferably, the drug is administered by one or more of the following methods: oral administration, injection, implantation, spraying and / or inhalation.

[0032] Preferably, the dosage form of the drug is one or more selected from the following: injection, oral solution, powder, tablet, granule, capsule, syrup, decoction, sustained-release preparation, enteric solvent, aerosol or suspension.

[0033] In a second aspect, the present invention provides a method for preventing and / or treating Alzheimer's disease, the method comprising: administering a preventively and / or therapeutically effective amount of a GPE analogue as shown in Formula I above or a pharmaceutically acceptable derivative thereof to a subject in need thereof.

[0034] The term "effective amount" refers to the amount or dosage of an active ingredient that provides the desired effect to the patient being diagnosed or treated by single or multiple administrations to the patient. The effective amount can be determined by the participating diagnostician as a person skilled in the art through known techniques and observations obtained under similar circumstances. In determining the effective amount or dosage of the active ingredient to be administered, the participating diagnostician should consider a variety of factors, including but not limited to: the species of the mammal; size, age and general health; the specific disease involved; the degree of involvement or severity of the disease; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability properties of the administered formulation; the selected dosage regimen; the use of concomitant drug therapy; and other relevant circumstances.

[0035] Beneficial Effects

[0036] The present invention provides the use of a GPE analogue as shown in Formula I above or a pharmaceutically acceptable salt, prodrug or hydrate thereof in the preparation of a drug for preventing and / or treating Alzheimer's disease. The inventors have confirmed through experiments on AD disease animal models that the GPE analogue as shown in Formula I can significantly improve the symptoms of cognitive impairment in AD disease mice, and even improve their cognitive level to a level close to normal; further, the inventors studied its mechanism of influence on AD disease pathology and found that the GPE analogue as shown in Formula I can significantly reduce the deposition of β-amyloid protein in the cerebral cortex and hippocampus of AD disease mice, thereby reducing its toxicity to nerve cells, and thus can prevent, alleviate, improve or treat AD disease or its symptoms, or delay the progression of AD disease, and is a very promising candidate therapeutic drug for Alzheimer's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] One or more embodiments are exemplarily described by the pictures in the accompanying drawings, and these exemplary descriptions do not constitute limitations on the embodiments. The special word "exemplary" here means "used as an example, embodiment or illustrative". Any embodiment described as "exemplary" here is not necessarily interpreted as being superior or better than other embodiments.

[0038] Figure 1 A schematic diagram showing the drug treatment and behavioral testing process for AD disease mice APP / PS1 in Example 1.

[0039] Figure 2 The Morris water maze experiment of Example 1 shows the escape latency of mice in each experimental group during the training phase; wherein the horizontal axis shows the training time, and the vertical axis shows the escape latency (s); * indicates: on the 5th day of training, compared with the AD model control group (i.e., APP / PS1 group), P<0.05.

[0040] Figure 3 The Morris water maze experiment of Example 1 shows the distance from each experimental group of mice to the target platform during the training phase; wherein the horizontal axis shows the training time, and the vertical axis shows the distance to the target platform (cm); * indicates: on the 5th day of training, compared with the AD model control group (i.e., APP / PS1 group), P<0.05.

[0041] Figure 4 The Morris water maze spatial exploration experiment of Example 1 shows the number of crossings of the target quadrant by mice in each experimental group after the target platform is hidden; wherein the horizontal axis shows the group, and the vertical axis shows the number of crossings in the target quadrant; * indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.05; *** indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.001; ns indicates that there is no significant difference between the two groups.

[0042] Figure 5 The Morris water maze spatial exploration experiment of Example 1 shows the residence time of mice in each experimental group in the target quadrant after the target platform is hidden; wherein the horizontal axis shows the group, and the vertical axis shows the residence time in the target quadrant; * indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.05; ** indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.01; ns indicates that there is no significant difference between the two groups.

[0043] Figure 6 The representative trajectory diagrams of the mice in each experimental group searching for the target platform in each quadrant after hiding the target platform in the Morris water maze spatial exploration experiment of Example 1 are shown.

[0044] Figure 7 Representative histological sections showing Aβ plaque deposition in the hippocampus and cerebral cortex of mice in each experimental group in Example 1.

[0045] Figure 8The density of Aβ plaques per square millimeter in the hippocampus of mice in each experimental group in Example 1 is shown; wherein the horizontal axis shows the group, and the vertical axis shows the density of Aβ plaques in the hippocampus (%); * indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.05; ** indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.01.

[0046] Fig. 9 The density of Aβ plaques per square millimeter in the cerebral cortex of mice in each experimental group in Example 1 is shown; wherein the horizontal axis shows the group, and the vertical axis shows the density of Aβ plaques in the cerebral cortex (%); *** indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.001; **** indicates: compared with the AD model control group (i.e., APP / PS1 group), P<0.0001. DETAILED DESCRIPTION

[0047] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described in conjunction with the embodiments below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0048] In addition, in order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. It should be understood by those skilled in the art that the present invention can also be implemented without certain specific details. In some embodiments, raw materials, elements, methods, means, etc. well known to those skilled in the art are not described in detail, so as to highlight the main purpose of the present invention.

[0049] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0050] The present invention is further described in detail below by way of examples.

[0051] Example 1: Effects of GLXC-15737 drug treatment on cognitive function of AD mice and its pathological mechanism

[0052] In this example, 6-month-old male APP / PS1 double transgenic mice (purchased from Beijing Weishanglide Co., Ltd.) were used as AD model mice, and C57BL / 6 male mice of the same age were used as wild mouse controls to study the improvement effect of the GPE analog GLXC-15737 (i.e., the GPE analog shown in Formula I, purchased from MecChemExpress, stored in a dark, dry place at -20°C) on cognitive impairment (including spatial memory and learning ability) in AD mice.

[0053] APP / PS1 double transgenic mice are constructed by gene editing technology. They co-express human-mouse chimeric amyloid precursor protein (APP) carrying the Swedish mutation (APPswe) and presenilin 1 mutant (PS1-dE9) lacking exon 9 under the drive of the prion protein promoter. This model is a widely recognized and used Alzheimer's disease (AD) research model in the field because it can stably simulate the core pathology of AD (Aβ deposition) and progressive cognitive deficits. Its pathological process is presented in stages:

[0054] (1) Characteristics of Aβ deposition: Initial deposition of β-amyloid protein (Aβ) plaques appears in the brain at 6 months of age, a large number of dense plaques form in the cortex and hippocampus at 9 months of age, and the plaque load reaches a plateau at 12 months of age;

[0055] (2) Cognitive dysfunction: Morris water maze behavioral testing showed that the spatial learning ability of 9-month-old APP / PS1 mice was significantly impaired, as manifested by prolonged escape latency, shortened target quadrant residence time, and decreased memory consolidation ability, which is highly consistent with the characteristics of early cognitive decline in AD patients.

[0056] The experimental groups are as follows:

[0057] 1) Low-dose administration group (i.e., APP / PS1+50 mg / kg GLXC-15737 group), which was treated by intraperitoneal injection of 50 mg / kg GLXC-15737 in saline solution into 6-month-old male APP / PS1 double transgenic mice;

[0058] 2) high-dose administration group (i.e., APP / PS1+100 mg / kg GLXC-15737 group), which was treated by intraperitoneal injection of 100 mg / kg GLXC-15737 in saline solution into 6-month-old male APP / PS1 double transgenic mice;

[0059] 3) wild-type mouse control group (i.e., WT group), which was treated by intraperitoneal injection of the same volume of normal saline;

[0060] 4) AD disease model control group (i.e., APP / PS1 group), which was treated by intraperitoneal injection of the same volume of normal saline into 6-month-old male APP / PS1 double transgenic mice;

[0061] Schematic diagram of drug treatment and behavioral testing process of mice in the above experimental groups. The treatment procedures are shown in Figure 1 .

[0062] Specifically, the treatment of mice in each experimental group is as follows:

[0063] Male APP / PS1 mice of similar body weight and 6 months old were selected and randomly divided into a disease model group, a low-dose administration group and a high-dose administration group, with 8 mice in each group. At the same time, 8 male wild-type C57BL / 6 mice of similar body weight and 6 months old were selected as the control group. The low-dose administration group and the high-dose administration group were given 50 mg / kg and 100 mg / kg of GLXC-15737 solution dissolved in normal saline by intraperitoneal injection daily, respectively, while the control group and the disease model group were given an equal amount of normal saline by intraperitoneal injection daily for 8 weeks.

[0064] Afterwards, Morris water maze was used to evaluate the spatial memory and learning ability of mice in each group, and brain tissue sampling and related histological tests were performed, as follows:

[0065] 1. Morris water maze test

[0066] A circular pool with a diameter of 100 cm and a height of 60 cm was used as the experimental device. A target platform with a diameter of 10 cm was set in the pool. The platform was placed in the northeast quadrant and 0.5 cm below the water surface. The water temperature in the pool was precisely controlled at 21±1℃, and black reference objects were attached along the wall of the pool to provide visual reference for the mice.

[0067] The experiment was carried out in two phases: the first phase was a positioning navigation test, scheduled for days 1-5; the second phase was a spatial exploration test, scheduled for day 6. The entire experiment was designed to test the learning and memory ability of mice for their sense of spatial position and direction (i.e., spatial positioning).

[0068] During the positioning navigation test, the mouse was slowly placed in the water facing the pool wall and given 60 seconds to find the hidden platform. During this process, the time required for the mouse to find the platform was recorded as the escape latency; at the same time, the distance from the mouse's entry point to the target exploration path, that is, the distance to the target platform, was accurately measured and recorded. If the mouse successfully found the platform within 60 seconds, it was allowed to stay on the platform for 20 seconds; if it failed to find the platform within the prescribed 60 seconds, the experimenter would gently place the mouse on the platform and also let it stay for 20 seconds. Each mouse was required to receive 4 training sessions per day, and the escape latency of each mouse on each training day was calculated by averaging the results of the 4 training sessions on that day.

[0069] During the spatial exploration test, the target platform was removed from the pool. Then, each mouse was slowly placed in the water from the southwest quadrant. During the experiment, the mice's stay time and number of crossings in the quadrant where the target platform was located within 60 seconds were recorded in detail to observe the mice's spatial learning ability.

[0070] During the entire water maze test, video tracking and analysis were performed using SMART 3 software (Panlab HARVARD, USA).

[0071] The results are as follows Figure 2-6 As shown, where:

[0072] Figure 2-Figure 3 The escape latency and distance to the target platform of mice in each experimental group during the training phase of the Morris water maze experiment are shown respectively; it shows that the escape latency and distance to the target platform of mice in the AD disease model group (i.e., APP / PS1 group) are significantly higher than those of the wild-type mouse control group (i.e., WT group), indicating that the AD model mice were successfully constructed; after AD mice were treated with different doses of GLXC-15737, compared with the AD disease model group, the escape latency and distance to the target platform of mice were significantly shortened in both the low-dose and high-dose groups.

[0073] Figure 4-Figure 5 The figures show the number of crossings and the time spent in the target quadrant by mice in each experimental group after hiding the target platform in the Morris water maze spatial exploration experiment, which show that the number of crossings and the time spent in the target quadrant by mice in the AD disease model group (i.e., APP / PS1 group) were significantly lower than those in the wild-type mouse control group (i.e., WT group), indicating that the AD model mice were successfully constructed. After AD mice were treated with different doses of GLXC-15737, compared with the AD disease model group, the time spent and the number of crossings by mice in the target quadrant were significantly increased in both the low-dose and high-dose groups.

[0074] Figure 6The data show the trajectories of mice in each experimental group in each quadrant in the Morris water maze spatial exploration experiment. After the target platform was hidden, the trajectories of the mice in each experimental group in search of the target platform in each quadrant showed that the trajectories of the wild-type mice (i.e., WT group) were mainly concentrated near the target area, and the activity paths were relatively concentrated. In contrast, the activities of the AD model mice (i.e., APP / PS1 group) were more dispersed, and the residence time in the target area was reduced, showing a significant decrease in spatial memory ability. The trajectories of the mice in the GLXC-15737-treated group were more concentrated, and they stayed more near the target area, close to the performance of the WT group. This shows that GLXC-15737 can significantly improve the spatial memory ability of APP / PS1 mice, bringing it to a level close to that of normal healthy mice.

[0075] The above results indicate that GLXC-15737 treatment can significantly improve the spatial memory and learning ability of AD mice, that is, improve the cognitive impairment of mice and enhance their cognitive ability.

[0076] 2. Brain tissue sampling and related histological examination

[0077] (1) Tissue sampling: After the water maze test, mice were deeply anesthetized and perfused with cold PBS solution. The brain was quickly removed and fixed in 4% paraformaldehyde at 4°C for 24 hours.

[0078] (2) Paraffin section: The fixed brain tissue was sliced ​​at different depths, dehydrated with gradient ethanol, and then embedded in paraffin. The section thickness was 5 μm for immunohistochemical staining analysis.

[0079] (3) Brain tissue immunostaining: After paraffin sections were dewaxed and hydrated, antigen retrieval was performed using sodium citrate buffer. Subsequently, 3% hydrogen peroxide was added for blocking for 30 minutes, and then anti-Aβ1-42 antibody (as primary antibody) was added and incubated at 4°C overnight. After washing the next day, horseradish peroxidase-labeled secondary antibody was added, and freshly prepared DAB color development solution was added for color development.

[0080] (4) Result analysis: The images collected under the microscope were analyzed using ImageJ software, and the density of β-amyloid plaques per square millimeter was counted. The results were expressed as the average percentage of plaque area per square millimeter.

[0081] The results are as follows Figure 7-9 As shown, where:

[0082] Figure 7 The representative tissue immunostaining results of Aβ plaques in the hippocampus and cerebral cortex of mice in each experimental group are shown; brown particles represent Aβ plaques; Figure 7It can be seen that there are almost no Aβ plaques in the hippocampus and cerebral cortex of wild-type mice (i.e., WT group). In contrast, a large amount of Aβ plaques were deposited in AD model mice (i.e., APP / PS1 group), which is consistent with the molecular phenotype of AD disease; and the Aβ plaque deposition in the GLXC-15737-treated group was significantly reduced compared with the AD model mice. In particular, the Aβ plaque deposition in the high-dose treatment group was close to that in the WT group, which shows that GLXC-15737 can significantly improve and reduce the Aβ plaques in the brains of AD mice, bringing them to a level close to that of normal healthy mice.

[0083] Figure 8 and Fig. 9 The Aβ plaque density per square millimeter in the hippocampus and cerebral cortex of mice in each experimental group is shown respectively; Figure 8 and Fig. 9 It can be seen that compared with the AD model mice (i.e., APP / PS1 group), the Aβ plaque density in the hippocampus and cerebral cortex of the GLXC-15737-treated mice was greatly reduced, especially in the high-dose treatment group, where the Aβ plaque density decreased several times.

[0084] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of a GPE analogue or a pharmaceutically acceptable derivative thereof as shown in Formula I below in the preparation of a medicament for preventing and / or treating Alzheimer's disease:

2. The use according to claim 1, characterized in that The pharmaceutically acceptable derivatives of the GPE analogs are pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof.

3. The use according to claim 2, characterized in that: The prodrug of the GPE analog is a drug that can be converted into the GPE analog in vivo.

4. The use according to claim 2, characterized in that: The salt of the GPE analog is a salt selected from the following salt types: hydrochloride, phosphate, sulfate, fumarate, succinate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, lactate, malate, maleate, glutarate, oxalate or succinyl hemiamine salt.

5. The use according to any one of claims 1 to 4, characterized in that: The treatment of Alzheimer's disease includes one or more of the following: (1) Slow down the progression of Alzheimer's disease; (2) Improve symptoms caused by Alzheimer's disease; Preferably, the treatment of Alzheimer's disease is to alleviate cognitive dysfunction caused by Alzheimer's disease.

6. The use according to any one of claims 1 to 5, characterized in that: The prevention and / or treatment of Alzheimer's disease is achieved through the following mechanism: reducing the deposition of β-amyloid protein.

7. The use according to any one of claims 1 to 6, characterized in that: The medicament comprises a preventive and / or therapeutically effective amount of the GPE analog or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient.

8. The use according to claim 7, characterized in that The effective preventive amount of the GPE analog or its pharmaceutically acceptable derivative is 40-60 mg / kg body weight, preferably 50 mg / kg body weight, and the effective therapeutic amount is 80-120 mg / kg body weight, preferably 100 mg / kg body weight.

9. The use according to any one of claims 1 to 8, characterized in that The administration method of the drug is one or more selected from the following: oral administration, injection, implantation, spraying and / or inhalation.

10. The use according to any one of claims 1 to 8, characterized in that The dosage form of the drug is one or more selected from the following: injection, oral solution, powder, tablet, granule, capsule, syrup, decoction, sustained-release preparation, enteric solvent, aerosol or suspension.

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