KR101846120B1 - Pharmaceutical composition for preventing or treating neurodegenerative disease comprising 6-formyl umbelliferone as active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating neurodegenerative disease, containing 6-formyl umbelliferone as an active ingredient. The 6-formyl umbelliferone significantly inhibits activities of cholinesterase enzymes and beta-secretase 1 (BACE1), and suppresses production of amyloid beta peptides, thereby being useful for treating neurodegenerative disease.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising 6-formyl umbelliferone as an active ingredient,

The present invention relates to a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising 6-formylmaveliferone as an active ingredient.

The elderly population of the world is increasing, and in 2000, the elderly population aged 65 and over entered the aging society, which is more than 7% of the total population. In 2026, the elderly population accounted for over 20% (2060 long-term financial prospect in 2015), the solution of geriatric diseases of the elderly population is emerging as an urgent social problem.

In particular, Alzheimer's disease, which accounts for about half of the senile dementia diseases, is currently one of the most important neurological diseases to be resolved in the aging society. The pathophysiological mechanism of Alzheimer's disease is not yet known, but the cholinergic hypothesis and the amyloid hypothesis are implicated. The cholinergic hypothesis is that Alzheimer's disease is caused by a markedly lower concentration of acetylcholine in certain parts of the brain (Zarotsky et al., 2003; Tricco et al., 2012). According to this, acetylcholine, a neurotransmitter hydrolyzed by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), may be an important cause of Alzheimer's disease (Hebert et al., 1995 ; Thies and Bleiler, 2012; Zarotsky et al., 2003). Thus, the hypothesis that acetylcholinesterase and butyrylcholinesterase inhibitors can be used as therapeutic agents for Alzheimer's disease (Adams et al., 1984).

In addition, the amyloid hypothesis is that amyloid beta (Aβ) beta peptide accumulates in the brain, resulting in Alzheimer's disease (Querfurth and Laferla, 2010). Amyloid beta peptides are not only known to be an important cause of Alzheimer's disease, but are also known to cause various diseases such as Parkinson's and diabetes (Zhao et al., 2004; Eichner et al., 2011). It has been reported that amyloid proteins that normally should be water-soluble, when aggregated into plaque form, normally interfere with normal neuronal functions in brain neurons, leading to Alzheimer's disease (Lambert et al., 1998 Kim et al., 2003; Kounnas et al., 2010).

The amyloid beta peptide is produced by the amyloid precursor protein (APP) under the action of the aspartate protease gamma-secretase and beta-secretase (BACE1) . In the amyloid hypothesis, beta-secretase (BACE1) activity increases in brain with sporadic Alzheimer's disease (Yang et al., 2003; Holsinger et al., 2002). It was reported that BACE1 knock-out mice can not produce amyloid beta peptides, suggesting that only BACE1 cleaves APP and produces amyloid beta peptides (McConlogue et al., 2007). It has been reported that BACE1 produces fibrils with excess toxicity of amyloid beta peptide, which leads to degeneration of nerve cells.

Drugs for treating Alzheimer's disease include tacrine (THA, black) and donepezil (red), known as inhibitors of acetylcholinesterase, and QUD and TMF, known as inhibitors of ACE1, There is a problem that there are side effects that are caused by nausea, vomiting and diarrhea. Therefore, it is urgent to develop drugs having excellent effects and few side effects.

1. M.Y. Ali, H.A. Jung, J.S. Choi, Anti-diabetic and anti-Alzheimer's disease activities of Angelica decursiva, Arch. Pharm. Res. 38 (2015) 2216-2227. 2. M.Y. Ali, S. Jannat, H.A. Jung, R.J. Choi, A. Roy, J.S. Choi, Anti-Alzheimer potential of coumarins from Angelica decursiva and Artemisia capillaris and structure-activity analysis, Asian Pac. J. Trop. Med. 9 (2016) 103-111. 3. S. Caffieri, F. Di Lisa, F. Bolesani, M. Facco, G. Semenzato, F. Dall'Acqua, M. Canton, The mitochondrial effects of novel apoptogenic molecules generated by psoralen photolysis as a crucial mechanism in PUVA therapy, Blood 109 (2007) 4988-4894.

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising 6-formyl umbelliferone as an active ingredient.

It is still another object of the present invention to provide a health functional food for preventing or ameliorating a degenerative neurological disease comprising 6-formyl umbelliferone as an active ingredient.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising 6-formyl umbelliferone having the structure represented by the following formula (1) as an active ingredient .

[Chemical Formula 1]

In one embodiment of the present invention, the 6-formylambeliferone may inhibit the activity of BACE1 (beta-secretase 1) and cholinesterase to inhibit the formation of beta-amyloid plaques.

In one embodiment of the present invention, the degenerative neurological disease may be any one selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease.

The present invention also provides a health functional food for preventing or ameliorating a neurodegenerative disease comprising 6-formyl umbelliferone having the structure represented by the following formula (1) as an active ingredient.

[Chemical Formula 1]

The 6-formyl umbelliferone according to the present invention significantly inhibits the activity of BACE1 and cholinesterase enzymes, thereby inhibiting the production of amyloid beta peptide, which is known to be an important factor in degenerative neurological diseases, Can be usefully used for the treatment of diseases.

Figure 1 shows the inhibitory effect of acetylcholinesterase on umbelliferone (A), 6-formylambeliferone (B) and 8-formylambelliferone (C).
2 shows the inhibitory effect of butylyl cholinesterase on umbelliferone (A), 6-formylambeliferone (B) and 8-formylambelliferone (C).
Fig. 3 shows the inhibitory effect of BACE1 on umbelliferone (A), 6-formylambeliferone (B) and 8-formylambelliferone (C).
Figure 4 shows Lineweaver-Burk and Dixon plots of the inhibitory effect of 6-formylmaveliferone on BACEl activity.
Figure 5 shows Lineweaver-Burk and Dixon plots of the inhibitory effect of 8-formyl mambelliferone on BACEl activity.
FIG. 6 is a graph showing the results of the determination of tacrine (THA, black), known as an inhibitor of acetylcholinesterase (THA, black) and dodecylbenzene A model of molecular docking with the active site of acetylcholinesterase for the phenol (donepezil, red) is shown.
FIG. 7 is a graph showing the effect of the inhibitors of amberlyferon (A), 6-formylambeliferone (B), 8-formylambelliferone (C), acetylcholinesterase inhibitor tacrine (THA, D) (donepezil, E) and acetylcholinesterase, respectively.
Figure 8 shows that BACE1 (red) and TMF (black), which are known as inhibitors of BACEl, and TMF (black), are known to be inhibitors of BACE1 Molecule interaction with the active site.
FIG. 9 is a graph showing the results of immunohistochemical staining for amberlycerol (A), 6-formylambeliferone (B), 8-formylambelliferone (C), tacrine (THA, D) ) And BACE1. ≪ / RTI >

The present invention relates to a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising 6-formyl umbelliferone having the structure represented by the following formula (1) as an active ingredient.

[Chemical Formula 1]

When the composition of the present invention is used as a medicament, the pharmaceutical composition comprising 6-formyl ebbeliperone as an active ingredient may be formulated into various oral or parenteral dosage forms at the time of clinical administration, But is not limited thereto.

Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and elixirs. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, Silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols), in addition to the active ingredient (s). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

The pharmaceutical composition comprising the 6-formyl mambelliferone of the present invention as an active ingredient can be administered parenterally, and parenteral administration can be carried out by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection All. In this case, in order to formulate a formulation for parenteral administration, a pharmaceutical composition containing 6-formylmaveliferone as an active ingredient is mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which is then administered in an ampule or vial unit Can be manufactured. The compositions may comprise sterilized and / or contain adjuvants such as preservatives, stabilizers, wettable or emulsifying accelerators, salts for controlling osmotic pressure and / or buffers, and other therapeutically useful substances, Or may be formulated according to the coating method.

The dose of the composition of the present invention to the human body may be varied depending on the age, body weight, sex, dosage form, health condition, and disease severity of the patient. When the patient is 60 kg body weight, And may be 0.01 to 500 mg / day, preferably 0.01 to 500 mg / day, and may be administered once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.

In order for the 6-formyl mambelliferone of the present invention to be used for prevention and improvement of such degenerative neurological diseases as described above, it may be prepared by various methods known in the field of food science or pharmacology, And may be prepared in any food form that can be ingested orally by mixing with a carrier, excipient, diluent or the like. Preferably in the form of beverage, ring, granule, tablet or capsule.

The health functional food of the present invention may further comprise ingredients that are conventionally added at the time of food production and which are pharmaceutically acceptable. For example, in the case of beverage preparation, one or more ingredients such as citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice and the like may be further contained in addition to the 6-formylmaveliferone of the present invention.

The amount that can be included as an active ingredient of the health functional food according to the present invention can be appropriately selected according to the age, sex, weight, condition, and symptom of a person who wants to prevent or improve the neurodegenerative disease, 0.01 g to 10.0 g per day. It is possible to obtain the effect of preventing and improving the degenerative neurological disease by ingesting the health functional food having such a content.

Hereinafter, the present invention will be described in more detail with reference to examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example 1. Materials and methods

1.1. From Jihwa  6- Formyl Umberly Peron's  detach

(2.7 kg) of the powder was extracted with methanol for 3 hours under reflux and cooling for 3 hours, and then concentrated under reduced pressure at 40 캜 or lower to obtain a methanol extract (864.32 g). The methanol extract was suspended in distilled water and then sequentially partitioned between dichloromethane (CH2Cl2), ethyl acetate (EtOAc) and n-BuOH (212.47 g), EtOAc (19.06 g) and n-BuOH 151.07 g) and a final fraction (434.32 g). The EtOAc fraction (19 g) was subjected to silica gel column chromatography using CH ₂ Cl ₂ -MeOH (10: 1) as a solvent to obtain 20 subfractions from F-1 to F-20, followed by F-6 (500 mg) The residue was subjected to silica gel column chromatography again using CH ₂ Cl ₂ -MeOH (15: 1) as a solvent to finally isolate an off-white powder 6-formyl uberifferone (30 mg). The structure of the compounds was determined by comparing the hydrogen and carbon nuclear magnetic resonance spectra with the literature (Caffieri et al., 2007).

Appearance of 6-formyl umbelliferone - light-white powder; ^{1 H NMR (400 MHz, DMSO-} d 6): H 11.7 (1H, brs, -OH), 10.24 (1H, s, -CHO), 8.03 (1H, s, H-5), 8.04 (1H, d , J = 9.6 Hz, H-4), 6.84 (1H, s, H-8), 6.32 (1H, d, J = 9.6 Hz, H-3); ^{13 C NMR (100 MHz, DMSO-} d 6): δ C 189.2 (-CHO), 163.4 (C-7), 159.5 (C-2), 158.7 (C-9), 144.4 (C-4), 130.0 (C-5), 120.4 (C-6), 113.1 (C-3), 111.96

1.2. 8- Formyl Umberly Peron's  synthesis

Under ice cooling, umbelliferone was dissolved in trifluoroacetic acid solution (2.0 g, 9.8 m mole), and urotropine (2.06 g, 14.69 m mole) was added slowly and heated under reflux for 12 hours. After the reaction, evaporate the solvent, add 30 mL of distilled water, and leave it under ice-cooling condition to produce a yellow precipitate. Filtered, dried and chromatographed on silica gel with hexane: ethyl acetate (10: 1) to give pale yellow 8-formyl eubelipernone (0.30 g, yield 15%). Forms of 8-formyl umbelliferone - Pale yellow powder; ^{1 H NMR (400 MHz, CDCl} 3): δ H 12.22 (1H, brs, -OH), 10.61 (1H, s, -CHO), 7.66 (1H, d, J = 9.6 Hz, H-4), 7.60 (1H, d, J = 8.8 Hz, H-5), 6.89 (1H, d, J = 8.8 Hz, H-8), 6.33 (1H, d, J = 9.6 Hz, H-3); ¹³ C NMR (100 MHz, CDCl ₃ ):? _C 192.94 (-CHO), 165.51 (C-7), 159.12 (C-2), 156.74 (C-6), 113.41 (C-8), 110.85 (C-3), 108.68

1.3. Choline esterase  (cholinesterase) inhibitory activity

The cholinesterase inhibitory activity measures the inhibitory activity of AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) using acetylthiocolchicine (ACh) and butyrylthiocholine (BCh) as substrates. 20 μl of 100 mM sodium phosphate buffer (pH 8.0), 20 μl of sample, and 20 μl of AChE (0.36 U) or BChE (0.36 U) were added to 96-well microplates and incubated at room temperature for 15 minutes. 10 μl of DTNB [ 5'-dithiobis (2-nitrobenzoic acid)] and 10 μl of the substrate ACh or BCh, and finally add 200 μl of the reaction solution into a 96-well plate. In this case, the enzyme reaction starts when DTNB and substrate ACh or BCh are added. The yellow 5-thio-2-nitrobenzoate anion, which is formed by the reaction of thiocholine and DTNB produced by enzymatic hydrolysis of ACh or BCh, VERSA max (Molecular Devices, CA, USA) at 412 nm for 15 minutes. The cholinesterase inhibitory activity of each test sample is represented by the IC ₅₀ value, which represents the concentration by which the hydrolysis of the substrates ACh and BCh is inhibited by 50% in μg / ml or μM. Berberine was used as a positive control. The cholinesterase inhibition% was determined by the following equation.

Inhibition (%) = [1- (A _sam / A _con ) / A _std ] x 100

A _sam : Absorbance of the sample

A _con : absorbance when the sample is added and the enzyme is not added

A _std : Absorbance without sample

1.4. BACE1  (β- secretase ) Active inhibition experiment

The inhibitory activity against beta-secretase, an enzyme involved in Alzheimer's disease, was performed according to the kit reagent method (BACE1 FRET assay kit, PanVera Co.). (50 mM sodium acetate, pH 4.5), BACE1 enzyme (1.0 U / mL), and substrate (750 nM Rh-EVNLDAEFK-Quencher in 50 mM ammonium bicarbonate) were dissolved in 10% RTI ID = 0.0 > 60 C < / RTI > When the two kinds of fluorophores (Rh-EVNLDAEFK-Quencher) were degraded by BACE1, a fluorescent donor (Rh-EVNL) was formed and the reaction product was detected by a microplate spectrofluorometer (Gemini EM) at 545 nm excitation and 585 nm , Molecular Devices, and Sunnyvale, CA, USA). BACE1 inhibition% was calculated by the following equation. BACE1 enzyme inhibition of each sample was expressed as IC ₅₀ value (μM).

Inhibition (%) = [1 - (S 60 - S 0) / (C 60 - C 0)] × 100

C ₆₀ : Fluorescence intensity (enzyme, buffer, substrate) of the control group after 60 minutes of reaction,

C ₀ : Immediately after mixing (0 min) Fluorescence intensity (enzyme, buffer, substrate)

S ₆₀ : Fluorescence intensity (sample, enzyme, buffer, substrate)

S ₀ : Immediately after mixing (0 min) Fluorescence intensity (sample, enzyme, buffer, substrate)

1.5. beta Secretase  ( BACE1 ) kinetic studies

To determine the inhibitory activity of BACE1, various concentrations of compound and substrate Rh-EVNLDAEFK-Quencher were prepared at concentrations of 750 nM, 375 nM and 250 nM. (10 μM, 2 μM, 0.4 μM; 8-formyl ambeleferone: 100 μM, 50 μM, 25 μM) and the substrate were incubated with various concentrations of compounds (Gemini EM, Molecular Devices, Sunnyvale, Calif., USA) at 545 nm excitation and 585 nm emission. The inhibition pattern was determined by Dixon plot and Lineweaver-Burk plot. The inhibition constant ( Ki ) of the inhibitor was determined by Dixon plot.

1.6. Of BACE1  Molecular docking simulation study

Docking studies were performed to determine the optimal binding site of the sample to BACE1. Human BACE1 inhibitor QUD (2-amino - {( 1 R) -1-cyclohexyl-2 - [(cyclohexylcarbonyl) amino] ethyl} -6-phenoxyquinazolin-3-ium): 2.5 Å of each of the (PDB ID 2WJO) Resolution structures with resolution were provided by the RCSB Protein Data Bank. For docking simulation, the QUD was removed and the protein was considered to be free of ligands. The water molecules were analyzed using Accelrys Discovery Studio 16.1 (DS, http://www.accelrys.com, Accelrys, Inc. San Diego, CA, USA) Lt; / RTI > The autodock 4.2.6 automated docking tool was used to attach polar hydrogen atoms to the protein, and the sites where QUD binds to the protein were the most suitable ligand binding sites. The three-dimensional structure of umbelliferone, 6-formylumbeliferone and 8-formylumbeliferone was drawn using Chemdraw Ultra 12.0 (CambridgeSoft, Cambridge, Mass., USA) and stored in the pdb format. Automated docking simulation was performed using the Autodock tools (ADT). Grid map was created by setting the grid box size to 126 × 126 × 126 points and setting the default spacing to 0.375 Å so as to completely contain the protein binding site. A model with the lowest energy value among the binding patterns of BACE1 residues and corresponding binding energies was regarded as the best molecular interaction. A known allosteric inhibitor, TMF (5,7,4'-trimethoxyflavone), was used to compare the binding residues and aspects. The results were analyzed using UCSF Chimera and LigPlot (v.1.4.5), and all docking simulations were performed using the Intel® Core ™ i5-6300HQ CPU @ 2.30 GHz (Windows 10 and 64-bit operating system).

Example  2. Umberly Peron , 6- Formyl Umberly Peron  And 8- Formyl Umberly Peron's  Effect of inhibitory activity on BACE1 and cholinesterase enzymes

The present inventors conducted an experiment to examine the inhibitory activity of umbelliferone, 6-formyl umbeliferone and 8-formyl uberiferone against BACE1 and cholinesterase enzymes. With berberine as a control compound, anti-cholinesterase activity was confirmed against uberferon, 6-formyl eubaryferon and 8-formyl eubelipron under in vitro conditions.

As a result, in the inhibitory activity against acetylcholinesterase obtained from eels (Table 1), umbeliferone showed a weak inhibitory activity with a 50% inhibitory concentration (IC ₅₀ ) of 105.48 ± 0.57 μM, Valericone and 8-formyl uberiferone showed high inhibitory activity as 16.70 ± 1.62 and 19.13 ± 0.57 μM. The control compound berberine was 0.74 ± 0.007 μM. All of these compounds showed a dose-dependent inhibitory activity against acetylcholinesterase (Fig. 1).

In addition, the inhibitory activity against butyrylcholinesterase (Table 1) was confirmed, and the 50% inhibitory concentration (IC ₅₀ ) of umbelliferone and 8-formyl uberifenone was 90.14 ± 0.02 and 87.67 ± 0.48 μM (Fig. 2). However, 6-formylmaveliferone showed a somewhat higher inhibitory activity (27.90 ± 3.43 μM) (FIG. 2). The control compound berberine was 9.81 ± 0.35 μM.

Inhibitory activity against beta- secrecase (BACE1) (Table 1) showed a very weak inhibitory effect, whereas when substituted with 6-formyl and 8-formyl, IC ₅₀ ) was as high as 1.31 ± 0.01 and 39.82 ± 0.31 μM (FIG. 3). In particular, 6-formylmaveliferone showed much higher activity than quercetin, the control group. The inhibition pattern for 6-formylmaveliferone against BACE1 enzyme was confirmed to be 2.27 from the Dixon plot and the Lineweaver-Burk plot for the non-competitive inhibition constant ( Ki ) , Figs. 4 and 5).

[Table 1]

^a IC ₅₀ value (μM) was calculated as a logarithmic curve and expressed as mean ± SEM from triplicate experiments.

^b determined by the Dixon plot.

^{c determined by the} Dixon plot and the Lineweaver-Burk plot.

^{d, e} positive control group

( - ) no test

Example  3. BACE1  Molecular docking studies on inhibitory activity

The present inventors have studied molecular docking of compounds and known inhibitors (QUD and TMF). According to the protein data bank (PDB), QUD is the most potent non-peptide competitive BACE1 inhibitor and TMF is a noncompetitive inhibitor.

As shown in Table 3 and FIG. 7A, the binding site with the highest binding energy (-5.4 kcal / mol) in the active site was found to be hydrogen bonding to the Asp32, the catalytic residue of the enzyme, in the hydroxyl group of uberperone. In addition, a van der Waals interaction was observed between the umbelliferone and the Lys75, Trp76, Val69, Phe108 and Ile 118 residues of the enzyme.

In contrast to umbeliferone, 6- and 8-formylambeliferone were not docked to the catalytic site of BACE1, which is consistent with an in vitro enzyme kinetics study. As shown in Fig. 9B, the Gly13 residue of BACE1 formed a hydrogen bond with the hydroxyl group and the formyl group of 6-formylambelliferone, respectively, and had a binding energy of -7.2 kcal / mol. Furthermore, it has been shown that hydrophobic binding between 6-formylmaveline and Ser10, Gly11, Tyr14, Val170, Thr232, Arg307, Pro308, Ala335 and Glu339 residues of BACE1 also plays an important role in binding to allosteric sites. A molecular docking model of 8-formyl ebbeliperone is shown in Figure 9C. In the 8-formylembeliferone-BACE1 complex, Ser10, Gly11, Gly13, Tyr14, Val170, Thr232, Arg307, Ala335, Val336 and Glu339 residues of the enzyme show hydrophobic interactions with 8- formylmaveliferone And hydrogen bonding was not observed. QUD interacted with BACE1 by forming four hydrogen bonds with Gly230 and Asp228, the catalytic residues, and Asp32. The enzymes Lys107, Lys75, Gly74, Leu30, Thr231, Val69, Tyr198, Ile226, Thr329, Gly34, Arg235, Ser35, Tyr71 and Ile118 residues were also found to be involved in the hydrophobic interaction between BACE1 and QUD. In the reported allosteric inhibitors TMF and BACE1 complex, the Gly11 residue of the enzyme formed a single hydrogen bond with the oxygen atom of TMF (Fig. 9E). In addition, hydrophobic interactions between TMF and Ser10, Tyr14, Thr232, Trp277, Glu303, Gln304, Leu306, Arg307, Pro308, Tyr320, Ala335, Val336 and Glu339 residues of the enzyme were predicted. As shown in FIG. 6, the docking results of the present inventors show that the bonding position of 6-, 8- formylmaveliferone to BACE1 is similar to that of TMF.

[Table 2]

^a Binding energy - refers to the binding affinity and binding affinity for the active site of the AChE enzyme.

^{b, c, d} The hydrogen bond from the enzyme-inhibitor complex and all amino acid residues are determined by the Autodockvina program.

[Table 3]

^a Binding energy - refers to the binding affinity and binding affinity for the active site of the AChE enzyme.

^{b, c, d} The hydrogen bond from the enzyme-inhibitor complex and all amino acid residues are determined by the Autodockvina program.

Claims (6)

A pharmaceutical composition for preventing or treating degenerative neurological diseases comprising 6-formyl umbelliferone having the structure of the following formula (1) as an active ingredient:
[Chemical Formula 1]

. The method according to claim 1,
Wherein said 6-formylambeliperon inhibits the activity of BACE1 (beta-secretase 1) and cholinesterase to inhibit the production of beta-amyloid plaques. The method according to claim 1,
Wherein the degenerative neurological disease is any one selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease. A health functional food for preventing or ameliorating a degenerative neurological disease comprising 6-formyl umbelliferone having the structure of the following formula (1) as an active ingredient:
[Chemical Formula 1]

. 5. The method of claim 4,
Wherein the 6-formyl mambelliferone inhibits the activity of BACE1 (beta-secretase 1) and choline esterase to inhibit the production of beta-amyloid plaques. 5. The method of claim 4,
Wherein said degenerative neurological disease is any one selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease.

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