KR20130015932A - Pharmaceutical composition for treating alzheimer's disease including low dose thazolidinedione - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing a thiazolidinedione-based drug for preventing and treating Alzheimer's disease is provided to enhance LRP1 expression and the discharge of beta-amyloid into the blood. CONSTITUTION: A pharmaceutical composition for treating neurological disorders contains a thiazolidinedione-based drug as an active ingredient. The thiazolidinedione-based drug includes rosiglitazone, pioglitazone, or troglitazone. The pharmaceutical composition enhances the LRP1 expression level in the cerebrovascular endothelial cells. The pharmaceutical composition enhances the absorption of beta-amyloid by LRP1. The composition is a capsule, a tablet, a granule, an injection, an ointment, a powder, or a beverage. A health functional food for preventing or treating neurological disorders contains a thiazolidinedione-based drug as an active ingredient.

Description

Pharmaceutical composition for treating Alzheimer's disease including low dose thazolidinedione}

The present invention relates to a pharmaceutical composition for preventing and treating Alzheimer's disease, which comprises a chiazolidinone-based medicament as an active ingredient.

Although the exact pathogenesis of Alzheimer's disease is unknown, studies to date indicate that the accumulation of beta-amyloid protein in the brain parenchyma reveals a characteristic pathological finding called 'aging group', resulting in a decrease in brain cell function. The amyloid hypothesis is the most widely accepted. Many scholars and multinational pharmaceutical companies are now working to develop drugs to prevent the accumulation of beta amyloid. According to a recent clinical study, there was no difference in the production of beta amyloid in the brain when compared to patients with Alzheimer's disease, but the release of beta amyloid into the bloodstream through the blood-brain barrier in Alzheimer's patients It was confirmed that it was reduced.

LDL receptor-related protein 1 (LRP1), which is expressed in vascular endothelial cells of the blood brain barrier, is a receptor that binds to various ligands and binds to beta amyloid and is responsible for transporting beta amyloid from the brain parenchyma to the blood. . Therefore, it is known that when the expression and function of LRP1 is increased, the rate of clearance of beta amyloid from the brain to the blood is increased, thereby effectively preventing the accumulation of beta amyloid in the brain parenchyma, and furthermore, it is known that it may be effective in the prevention and treatment of Alzheimer's disease.

On the other hand, thiazolidinedione-based drugs are commonly referred to as glitazone-based drugs and are oral hypoglycemic agents known to effectively reduce blood sugar by improving insulin resistance in diabetic patients. Recently, there have been efforts to use chiazolidinone-based drugs in the treatment of Alzheimer's disease, and some studies have proven effective and have been conducted in large-scale phase 3 studies, but the results have been found to be ineffective. The theoretical background of the use of these drugs is that many new drugs that inhibit the production of beta amyloid have been developed. However, the effects of these drugs have not been confirmed in actual clinical trials. It was an attempt to use it to treat Alzheimer's disease. However, according to the above-mentioned studies, considering the fact that the difference between Alzheimer's disease patients and normal people is not the production of beta amyloid, but the discharge of beta amyloid through the cerebrovascular endothelial cells, drug therapy is needed. To date, no drug has been developed under these mechanisms, and most new drugs are drugs that inhibit the production of beta amyloid and the formation of senescence plaques, or that are expected to increase indirect emissions using antibodies against beta amyloid.

Accordingly, the present inventors have made intensive efforts to develop a drug that can treat Alzheimer's disease. As a result, the present inventors have used chiazolidin-dione-based drugs that are currently used as oral hypoglycemic agents at low doses of several tens to hundreds of minutes. It was confirmed that the expression of LRP1, a beta amyloid transporter of cerebrovascular endothelial cells, may be increased and the intracellular migration of beta amyloid may be increased. In addition, the mechanism was confirmed to be a direct increase through the PPRE sequence in the promoter of the LRP1 gene to complete the present invention.

It is an object of the present invention to provide a pharmaceutical composition for treating neurological disorders, comprising, as an active ingredient, a chijolidinedione-based medicament maintaining a blood concentration of 0.1 to 100 nM.

The present invention provides a pharmaceutical composition for treating neurological diseases, comprising, as an active ingredient, chiazolidindione-based medicaments maintaining a blood concentration of 0.1 to 100 nM in order to achieve the above object.

In the present invention, the chiazolidinone-based medicament includes rojiglitazone, pioglitazone and troglitazone, but is not limited thereto and may include all of the chiazolidinone-based drugs to be developed in the future. The composition may be in the form of capsules, tablets, granules, solutions, injections, ointments, powders or beverages.

In the present invention, the pharmaceutical composition may be characterized by increasing the expression level of LRP1 in cerebrovascular endothelial cells, the pharmaceutical composition may also be characterized by increasing the absorption of beta amyloid by LRP1.

In the present invention, the pharmaceutical composition may be characterized by targeting a human, and the neurological disease may be characterized by Alzheimer's disease.

Routes of administration of the pharmaceutical compositions according to the invention are not limited to these, but are oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Sublingual or rectal. Oral or parenteral release is preferred. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.

The pharmaceutical compositions of the present invention may be used in the form of oral dosage forms, such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. have. The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable

In the case of oral administration, a binder, a suspending agent, a disintegrating agent, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a coloring agent, a flavoring agent, and the like can be used.In the case of an injection, a buffer, a preservative, a painless agent, a solubilizer, Isotonic agents, stabilizers and the like can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives and the like can be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in a variety of ways by mixing with pharmaceutically acceptable carriers as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms. have. Others can be formulated into solutions, suspensions, tablets, hgksdir, capsules, sustained release preparations and the like.

Examples of suitable carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose,

Microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.

The present invention may have the form of a sustained release formulation. Sustained release preparations are intended to sustain drug efficacy by delaying the release of a drug, and mean a preparation form that can maintain the concentration of the drug for a certain time or for a certain period of time. Sustained release formulations in the present invention may include diluent carriers commonly used in the pharmaceutical field for the formulation of oral solid preparations. Examples of such diluent carriers include lactose, dextrin, starch, microcrystalline cellulose, calcium carbonate, sugars and silicon dioxide, and other lubricants such as zinc stearate or magnesium to increase fluidity, or other compounds usable in the pharmaceutical field. Adjuvant may also be included.

The pharmaceutical compositions of the present invention vary depending on a number of factors, including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination and severity of the particular disease to be prevented or treated, of the specific compound employed. The dosage of the pharmaceutical composition may be appropriately selected by those skilled in the art depending on the patient's condition, weight, degree of disease, drug form, route of administration and duration, and 0.0001 to 50 mg / kg or It may be administered at 0.001 to 50 mg / kg. The administration may be administered once a day or may be divided several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.

In addition, the present invention provides a health functional food comprising the pharmaceutical composition and a food acceptable acceptable food supplement additive exhibiting a prophylactic and therapeutic effect of neurological diseases. Examples of foods to which chiazolidinedione-based drugs can be added include various foods, beverages, gums, teas, vitamin complexes, and health functional foods, and include pills, powders, granules, tablets, capsules, and the like. Available in form.

It may also be added to beverages for the purpose of preventing and treating neurological diseases. At this time, the amount of the drug of the chiazolidinedione-based in the food or beverage, generally in the case of the health food composition of the present invention can be added to 0.0001 to 100% by weight or 80% by weight or less of the food, the health beverage composition It may be added in a ratio of 0.0001 to 10 g or 5.0 g or less based on 100 ml.

The health beverage composition of the present invention is not particularly limited in the liquid component except for containing the fraction as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Examples of such natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like and xylitol, sorbitol, erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1-20 g, or about 5-12 g per 100 ml of the composition of the present invention.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and enhancers (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof. , Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is generally selected from 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

The use of the drug of the chiazolidinedione series according to the present invention at low doses increases the expression of LRP1, thereby increasing the release of beta amyloid from the brain parenchyma into the blood.

Figure 1 shows the effect of rosiglitazone on the expression of LRP1 in cerebrovascular endothelial cells.
Figure 2 shows the real-time PCR and immunoblotting results for the expression level of LRP1 in cerebrovascular endothelial cells according to the concentration of rosiglitazone.
Figure 3 shows the absorption capacity of beta amyloid in cerebrovascular endothelial cells according to the concentration of rosiglitazone.
Figure 4 shows the activity of the LRP1 promoter in cerebrovascular endothelial cells according to the concentration of rosiglitazone.
Figure 5 shows the effect of pioglitazone, another drug of the chiazolidinedione series on the expression of LRP1 in cerebrovascular endothelial cells.

Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Cell Culture and Preparation

Human brain microvascular endothelial cells (HBMECs, ScienCell, San Diego, Calif.) Are placed in fibronectin-coated dishes and 5% fetal bovine serum and endothelial cell grwoth supplement (ECGS) according to the manufacturer's instructions. It was cultured in the endothelial cell medium containing. Rosiglitazone (Rosiglitazone, GlaxoSmithKline, Brentford, Middlesex, UK) and Pioglitazone (Dakeda pharmaceutical, Osaka, Japan) were prepared in DMSO and stored at minus 20 degrees. HBMECs were incubated with various concentrations of rosiglitazone for 48 hours with stock solution added to the medium. Final DMSO concentration in the culture medium was adjusted to 0.5% (v / v).

RNA  And complementary DNA Preparation of

Total RNA was isolated from HBMECs using Trizol reagent (Invitrogen) and then quantified by nanodrop (ND-1000, DM science, Korea). After RNA extraction, 4 μl of RNA was treated with 1U DNase I to remove all contaminated DNA. DNase treated RNA was used to synthesize cDNA using MMLV reverse transcriptase (Promega, Madison, Wis.): 1 μl of oligo dT primers in 4 μl of RNA in 5 × MMLV buffer, 2.5 mM of each dNTP, 1 U It was added with a RNasin ribonuclease inhibitor and MMLV reverse transcriptase (200 units). cDNA was stored at minus 20 ℃.

Quantitative RT - PCR

Real-time quantitative RT-PCR analysis of various genes was performed with ABI 7500 (Applied Biosystems, Foster City, CA). All Taqman assays were performed using the following primers and probes: β-actin (Hs99999903_m1), LRP1 (Hs00233856_m1). PCR reactions were performed three times with a final volume of 20 μl according to the manufacturer's instructions. For each analysis, dilution series of cDNA samples for genes were analyzed to obtain a standard curve. Data was analyzed using Sequence Detector 1.7 software. β-actin was used as an internal standard for variability control and the results were expressed as the relative gene expression ratio of β-actin.

Immunoblot analysis

Subsamples of cell lysates (Thermo Scientific, Waltham, Mass.) Were denatured under reducing conditions (1.75% SDS, 15 mM 2-mercaptoethanol; 5 min at 100 ° C.), followed by SDS-PAGE and immunoblot analysis. To observe LRP1, nitrocellulose membranes were incubated with anti-LRP1 antibodies (rabbit monoclonal IgG, Epitomics, Burlingame, Calif.) (1: 1,500, overnight at 4 ° C), and goat anticoated with horseradish peroxidase. Incubated with -rabbit IgG (1: 5,000, Santa Cruz Biotechnology) for 1 hour. Immunolabeling was observed with the ECL Western Blotting Assay System (Thermo Scientific). LRP immunoreactivity was normalized to total protein as determined by the Bradford assay (Sigma-Aldrich). Β-actin activity observed with monoclonal anti β-actin antibody (1: 5,000, Sigma-Aldrich) and goat anti-rabbit IgG (1: 5,000, Santa Cruz Biotechnology) combined with horseradish peroxidase was a loading control. Was used.

Beta Amyloid Assay

Synthetic peptide beta amyloid (1-40) and beta amyloid (1-42) HiLite were purchased from Anaspec (San Jose, Calif.) And reconstituted in 1% NH4OH. To avoid aggregation, reconstitution and dilution were performed prior to the experiment. HBMEC cells were treated with beta amyloid (1 μM) and incubated at 37 ° C. for 1 hour in complete medium. To determine intracellular beta amyloid accumulation, cells were washed three times with PBS and lysed with 0.2% sodium dodecyl sulphate in water. Fluorescence in cell lysates and media was measured with a Berthold fluorometer (Berthold, Wildbad, Germany) and values were normalized to the amount of protein from the cell lysate and the fluorescence in the media.

LRP1  Reporter gene composition

LRP1 reporter gene comprising peroxisome proliferator response element (PPRE), the promoter region of LRP1, was constructed with reference to previous studies (Gauthier et al., J Biol Chem, 2003. 278 (14): p. 11945-53). 5'-flanking region of 1.9 kb LRP through PCR amplification using LRP-BAC structure (Source BioScience imaGenes, Berlin, Germany) and primer sets (5'-GCAACGAGCTCCGTAAAAGGGGGAAG-3 'and 5'-GCAGCAGATCTTTCCCCGGACTGAAG-3') Was prepared. Then, the prepared fragment was subcloned into the Sac I and Bgl I positions of the luciferase reporter vector pGL3-Basic (Promega), which was named pGL3-PPRE.

Transient transfection analysis ( Transient transfection assays )

Prior to transfection, HBMECs were seeded in 1.5-105 cells / well density in 6-well plates. 90% fusion cells were combined with 4 μg of firefly luciferase reporter vector (pGL3-basic or pGL3-PPRE) using Lipofectamin 2000 (Invitrogen, Carlsbad, Calif.) And 0.25 μg Renilla luciferase with reporter vector pRL-CMV (Promega). Transfection was performed. The medium was replaced with growth medium 4 hours after transfection, and the cells were then treated with various concentrations of rosiglitazone. After 48 hours, cells were scraped in 250 μl of reporter lysis buffer (Promega) and stored on ice until analysis. Luciferase activity from both LRP constructs and Renilla (pRL-CMV) proteins was measured using a dual luciferase reporter assay system (Promega) and recorded using a Berthold luminometer (Berthold, Wildbad, Germany). . Renilla luciferase activity was used to standardize transfection efficiency.

Statistical analysis

All statistical analyzes were performed with SPSS software (version 18.0; SPSS, Chicago, IL) and the values are expressed as mean ± SE. Statistical comparisons between groups were performed by t-test or 1-way analysis of changes, and p <.05 dml data values were determined to be important.

Rosiglitazone  According to the capacity LRP1  Gene expression level check

In order to analyze the effect of rosiglitazone on the expression of LRP1 in cerebrovascular endothelial cells, rosiglitazone was treated for 48 hours at various concentrations. As a result, it was confirmed that rosiglitazone increased the amount of LRP1 protein of cerebrovascular endothelial cells in a concentration-dependent manner until the concentration was 10 nM (FIG. 1). In addition, the results of quantitative RT-PCR and immunoblotting according to various concentrations of rosiglitazone treatment confirmed that rosiglitazone increased LRP1 mRNA and protein expression in cerebrovascular cells until the concentration was 10 nM (FIG. 2). However, the concentration of LRP1 mRNA and protein was not changed compared to the control at a concentration of 20 nM or more of rosiglitazone (FIG. 2).

Rosiglitazone  According to the capacity LRP1 Beta amyloid by Absorption capacity  Confirm

In order to confirm the function of LRP1 increased by rosiglitazone, the uptake of beta amyloid in cerebrovascular endothelial cells was measured. As a result, uptake of beta amyloid 40 and beta amyloid 42 was increased until the rosiglitazone concentration was 5 nM, and it was confirmed that it was stabilized at 10 nM (FIG. 3). In addition, it was confirmed that the concentration of rosiglitazone did not affect the absorption of beta amyloid at all compared to the control group.

In rosiglitazone  by LRP1  Confirmation of promoter activation

In order to confirm the mechanism of upregulation of LRP1 by rosiglitazone, a reporter assay was performed on cerebrovascular endothelial cells using the LRP1 promoter gene containing a PPRE sequence. Reporter analysis in cerebrovascular endothelial cells showed that LRP1 promoter activity was increased by treatment of rosiglitazone in a concentration-dependent manner until the concentration of rosiglitazone was 10 nM (FIG. 4). However, the activity of the LRP1 promoter did not increase at a concentration of 20 nM or more of rosiglitazone.

Pioglitazone  According to the capacity LRP1  Gene expression level check

In order to confirm that the effect of increasing LRP1 of vascular endothelial cells is not limited to rosiglitazone among chiazolidinedione series drugs, pioglitazone was treated to cerebrovascular endothelial cells at various concentrations for 48 hours. As a result, it was confirmed that pioglitazone increased the amount of LRP1 protein of cerebrovascular endothelial cells in a concentration-dependent manner until the concentration was 50 nM (FIG. 5). However, at the concentration of pioglitazone of 100 nM or more, the expression level of LRP1 mRNA and protein did not change compared to the control (Fig. 5).

Therefore, in view of the contents of Examples 1 to 4, the expression of LRP1 in cerebrovascular endothelial cells at the blood concentration of 0.1 to 100 nM of the chiazolidinedione-based drugs was increased, and the beta amyloid uptake by LRP1 was increased. It can be seen that it is effective in the prevention and treatment of neurological diseases including Alzheimer's disease.

Examples of formulations for the composition of the present invention are illustrated below.

Formulation Example 1 Preparation of Injection

Rosiglitazone ........................................ 10 mg

Sterile Distilled Water for Injection ...

pH adjuster ...

Injectables were prepared by mixing the above ingredients, filling a 2 ml ampoule and sterilizing according to a conventional method.

Formulation Example 2: Preparation of tablets

Rosiglitazone .................................. 10 mg

Lactose ............... 125 mg

Microcrystalline cellulose ... 75 mg

Magnesium Stearate ...............

The tablets were prepared by mixing the above components and tableting according to a conventional method for producing tablets.

Formulation Example 3 Preparation of Capsule

Rosiglitazone ................................. 10 mg

Lactose ............... 125 mg

Starch ............... 125 mg

Talc ..............................

Magnesium Stearate ...............

The capsules were prepared by mixing the above components and filling the capsules according to a conventional method for preparing capsules.

Formulation Example 4 Preparation of Liquid

Rosiglitazone ................................. 10 mg

Min .......................................... 20 g

Isomerized sugar ......................................... 20 g

Lemon Flavor ......................

Purified water was added and the above components were mixed according to a conventional method for preparing a liquid to prepare a liquid.

Formulation Example 5 Preparation of Health Food

Rosiglitazone ........................................ 10 mg

Vitamin A Acetate ......... 70 μg

Vitamin E ................................... 1.0 mg

Vitamin B1 ................................. 0.13 mg

Vitamin B2 ..................... 0.15 mg

Vitamin B6 .................. 0.5 mg

Vitamin B12 .................. 0.2 mg

Vitamin C ......................................... 10 mg

Biotin ......................................... 10 μg

Nicotinamide ........................................ 1.7 mg

Folic acid ......................................... 50 ㎍

Calcium Pantothenate ......................................... 0.5 mg

Ferrous Sulfate ......... 1.75 mg

Zinc Oxide ........... 0.82 mg

Magnesium Carbonate ............... 25.3 mg

Although the composition ratio of the rosiglitazone and the vitamin and mineral mixture is mixed with a component suitable for a health food in a preferred embodiment, the composition ratio may be arbitrarily modified. It was prepared according to a conventional health food production method.

Formulation Example 6 Preparation of Healthy Drinks

Rosiglitazone ........................ 10 mg

Citric Acid ......................................... 1000 mg

Oligosaccharide ... 20 mg

Taurine ........................... 100 mg

Purified water was added to adjust the total volume to 900 ml. It was prepared according to the conventional healthy beverage manufacturing method.

Although the composition ratio is a composition suitable for a preferred beverage in a preferred formulation example, the compounding ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

As described above in detail a specific part of the content of the present invention, for those skilled in the art, such a specific description is only a preferred embodiment, which is not limited by the scope of the present invention Will be obvious. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

A pharmaceutical composition for treating neurological diseases, comprising, as an active ingredient, chiazolidinedione-based drugs that maintain a blood concentration of 0.1 to 100 nM.
The method of claim 1,
The pharmaceutical composition of the chiazolidinedione series is any one selected from the group consisting of rosiglitazone, pioglitazone and troglitazone.
The method of claim 1,
The pharmaceutical composition is a pharmaceutical composition for treating neurological disease, characterized in that to increase the expression level of LRP1 in cerebrovascular endothelial cells.
The method of claim 1,
The pharmaceutical composition is a pharmaceutical composition for treating neurological disease, characterized in that to increase the absorption of beta amyloid by LRP1.
The method of claim 1,
The composition is a pharmaceutical composition for treating neurological diseases, characterized in that the capsule, tablets, granules, injections, ointments, powder or drink form.
The method of claim 1,
The pharmaceutical composition is a pharmaceutical composition for treating neurological disease, characterized in that the human.
The method of claim 1,
The neurological disease is a pharmaceutical composition for treating neurological disease, characterized in that Alzheimer's disease.
Health functional foods for the prevention or improvement of neurological diseases, comprising as an active ingredient a drug of the chiazolidinedione series to maintain a blood concentration of 0.1 to 100 nM.
The method of claim 8,
The chiazolidinone-based drugs are any one selected from the group consisting of rosiglitazone, pioglitazone and troglitazone, the health functional food for preventing or improving neurological diseases.
The method of claim 8,
The health functional food is a health functional food for the prevention or improvement of neurological diseases, characterized in that to increase the expression level of LRP1 in cerebrovascular endothelial cells.
The method of claim 8,
The health functional food is a health functional food for the prevention or improvement of neurological disease, characterized in that to increase the absorption of beta amyloid by LRP1.
The method of claim 8,
The health functional food is a capsule, tablets, granules, powder or a beverage for preventing or improving neurological disease, characterized in that the health functional food.
The method of claim 8,
The neurological disease is a health functional food for the prevention or improvement of neurological disease, characterized in that Alzheimer's disease.

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