KR20190023757A - Use of pkr inhibitors for treatment of alzheimer's disease - Google Patents

Abstract

The present invention relates to a therapeutic agent for Alzheimer′s disease capable of inhibiting the memory deficiency of Alzheimer′s disease by restoring damage to fundamental cellular mechanisms of Alzheimer′s disease. The therapeutic agent, in all of inherited Alzheimer′s disease caused by Aβ accumulation and mutations, can restore and enhance long-term potentiation (LTP) deficiency, long-term memory deficiency, contextual fear memory deficiency, and synaptic plasticity by PKR inhibitiors, therefore unlike existing therapeutic agents, it is possible to be used as the therapeutic agent for treating the memory deficiency caused by Alzheimer′s disease by inhibiting the same, which can restore and enhance fundamental cellular mechanisms of learning and memory.

Description

USE OF PKR INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE BACKGROUND OF THE INVENTION [0001]

The present invention relates to the use of a PKR inhibitor for the treatment of Alzheimer's disease, and relates to a therapeutic agent for Alzheimer's disease capable of inhibiting the memory deficit of Alzheimer's disease by restoring damage to essential cell machinery of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive deficiency and synaptic dysfunction, and there is no effective treatment at this stage. Genetic studies have confirmed that mutations in gene sets such as APP , PSEN1 and PSEN2 are associated with early-onset familial AD (FAD) (Goate et al., 1991; Levy-Lahad et al. 1995; Schellenberg et al., 1992). APP encodes an amyloid beta (A [beta]) precursor protein, and PSEN1 and PSEN2 encode presenilin-1 and presenilin-1, respectively. This protein is involved in the Aβ pathway and consequently supports the hypothesis that Aβ accumulation in the brain is important for AD (Hardy and Higgins, 1992). In addition to the accumulation of A [beta], hyper-phosphorylation of tau is well known as a typical characteristic of another AD (Duyckaerts et al., 2009). Interestingly, both Aβ accumulation and over-phosphorylation of tau are controlled by eukaryotic translation initiation factor 2α (Chang et al., 2002; O'Connor et al., 2008). Over-phosphorylation of eIF2α at the 51st serine (Ser) was observed in several AD mouse models as well as in the brain of post-AD patients (Devi and Ohno, 2013, 2014; Ma et al., 2013; Mouton-Liger et al., 2012). It has also been shown that A [beta] treatment induces phosphorylation of eIF2 [alpha] in cultured neurons (Mamada et al., 2015).

Phosphorylation of eIF2α inhibits normal mRNA translation but enhances the translation of specific mRNA groups such as BACE1 (β-site APP cleaving enzyme 1) and ATF4 (activating transcriptional factor 4), while cAMP responsive element binding protein (CREB) (Mamada et al., 2015; Ohno, 2014; Tanokashira et al., 2017). CREB is essential for organ-memory formation and long-term synaptic plasticity (Bartsch et al., 1998; Bourtchuladze et al., 1994; Gonzalez and Montminy, 1989; Reduction of eIF2a phosphorylation in wild-type mice improved long-term potentiation (LTP) and long-term memory by reducing ATF4 translation (Costa-Mattioli et al., 2007).

In addition to eIF2α, double-stranded RNA-activated protein kinase (PKR), one of the phosphorylases of eIF2α, was highly phosphorylated in AD brain (Chang et al., 2002; Dumurgier et al., 2013; Mouton-Liger et al ., 2012). When PKR binds to ATP and dsRNA, it is activated through autophosphorylation (Zhang et al., 2001). Genetic reduction of the other phosphorylating enzymes eIF2a, PERK and GCN2 improved AD-related phenotypes in synaptic plasticity and behavior in AD mouse models such as APP / PS1 and 5XFAD mice (Devi and Ohno, 2014; Ma et al. , 2013) (but also see (Devi and Ohno, 2013)). However, the pharmacological inhibitory effect of PKR on synaptic plasticity and memory deficits in the AD mouse model is not yet clear.

The present invention is based on the finding that PKR inhibition can increase synaptic plasticity and subsequently improve memory deficits in later stages of the AD mouse model, thereby providing synaptic plasticity associated with impairment of underlying cell mechanisms, It is an object of the present invention to provide a PKR inhibitor as a therapeutic agent for inhibiting memory deficiency of Alzheimer's disease by restoring long-term synergism (LTP).

In order to achieve the above object, the present invention provides a pharmaceutical composition for treating Alzheimer's disease (AD) comprising as an active ingredient a double-stranded RNA-activated protein kinase (PKR) inhibitor.

According to the present invention, it is possible to restore and enhance long-term potentiation (LTP) deficiency, long-term memory deficiency, contextual fear memory deficiency, and synaptic plasticity through PKR inhibition in both hereditary Alzheimer's disease caused by Aβ accumulation and mutation And it is a method of recovering and promoting the fundamental cell mechanism of learning and memory unlike the therapeutic agent for the purpose of eliminating the existing Aβ, so that the memory deficiency by Alzheimer's disease can be treated.

Fig. 1 is a diagram showing the obtained oligomer A? _1-42 by Western blotting.
FIG. 2 shows the effect of treatment with PKR inhibitor on memory deficits of Alzheimer's model mice caused by A? Or mutations by an object recognition test (NOR).
FIG. 3 shows the recovery (improvement) effect of PKR inhibitor on LTP deficiency induced by A? _1-42 in the hippocampus.
Figure 4 shows the effect of PKR inhibitor on the recovery of the contextual fear memory deficit in 5XFAD mice.
FIG. 5 is a graph showing the recovery effect of hippocampus synaptic plasticity in 5XFAD mice through LTP deficiency recovery (recovery) effect.

Hereinafter, the present invention will be described in detail with reference to embodiments of the present invention. It should be understood, however, that the invention is not limited thereto and that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents. .

In one aspect, the present invention relates to a pharmaceutical composition for the treatment of Alzheimer's disease (AD) comprising a double-stranded RNA-activated protein kinase (PKR) inhibitor as an active ingredient.

In one embodiment, the PKR inhibitor may be selected from the group consisting of nucleic acids, peptides, antibodies and compounds that inhibit PKR expression or protein activity, wherein the nucleic acid is selected from the group consisting of antisense nucleotides, microRNA, siRNA, shRNA, aptamer ), LNA (locked nucleic acid), PNA (peptide nucleic acid), and morpholino.

In one embodiment, the PKR inhibitor may be an inhibiting natural product of its activity or a compound isolated therefrom, more preferably a compound of formula (PKR inhibitor C16)

In one embodiment, the compound of Formula 1 may be administered in an amount of 0.001 to 1 mg / kg, preferably administered by intraperitoneal administration.

In one embodiment, the Alzheimer ' s disease can be Alzheimer ' s disease caused by A [beta] _1-42 accumulation or familial Alzheimer's disease (FAD) by gene mutation.

In one embodiment, the Alzheimer's disease can be Alzheimer ' s dementia, memory deficit, synaptic plasticity deficiency, long-term potentiation deficiency or memory deficit disorder.

In one embodiment, PKR inhibitors of the present invention simply, unlike the conventional treatment was to remove the Aβ _1-42, therefore brought recovery and promotion of fundamental cellular mechanisms of synaptic plasticity in learning and memory, independently of the removal of the Aβ _1-42 It is possible to treat Alzheimer's dementia associated with Alzheimer's disease, memory deficit, synaptic plasticity deficiency, long-term potentiation deficiency or impairment of cell machinery causing memory deficit disorder Do.

As used herein, the term " expression or inhibition of activity " means that the function of a target gene or a target protein is degraded. Preferably, the target gene expression or the function of the target protein is undetectable or non- It means to exist.

As used herein, the term " antisense nucleotide " refers to a nucleotide sequence that hybridizes (hybridizes) to a complementary base sequence of DNA, immature-mRNA or mature mRNA, as defined in the Watson- . The nature of antisense nucleotides that are specific for the target sequence makes them exceptionally multifunctional. Because antisense nucleotides are long chains of monomeric units they can be readily synthesized against the target RNA sequence. Many recent studies have demonstrated the utility of antisense nucleotides as biochemical means to study target proteins (Rothenberg et al., J. Natl. Cancer Inst., 81: 1539-1544, 1999). The use of antisense nucleotides can be considered as a novel type of inhibitor since there has been much progress in the field of oligonucleotide chemistry and in the field of nucleotide synthesis showing improved cell adsorption, target binding affinity and nuclease resistance.

As used herein, the term " siRNA (small interfering RNA) " refers to short double-stranded RNA capable of inducing RNAi (RNA interference) phenomenon through cleavage of a specific mRNA. The siRNA is composed of a sense RNA strand having a sequence homologous to the mRNA of the target gene and an antisense RNA strand having a complementary sequence, and a double strand having a sense sequence complementary to the base sequence of the PKR gene Any RNA molecule can be used. A sense RNA strand having a sequence homologous to the mRNA of the target gene and an antisense RNA strand having a sequence complementary thereto. siRNA is provided as an efficient gene knock-down method or as a gene therapy method because it can inhibit the expression of a target gene.

The term " antibody " used in the present invention can be used either as prepared through injection of anti-PKR or commercially available. In addition, the antibody includes a polyclonal antibody, a monoclonal antibody, and a fragment capable of binding to an epitope. Polyclonal antibodies can be produced by conventional methods of injecting the PKR into an animal and collecting blood from the animal to obtain serum containing the antibody. Such polyclonal antibodies can be purified by any method known in the art and can be made from any animal species host such as goats, rabbits, sheep, monkeys, horses, pigs, cows, dogs and the like. Monoclonal antibodies can be prepared using any technique that provides for the generation of antibody molecules through the cultivation of continuous cell lines. Such techniques include, but are not limited to, hybridoma technology, human B-cell hybridoma technology, and EBV-hybridoma technology (Kohler G et al., Nature, 256: 495-497, 1975; Coto SP et al., Proc. Natl. Acad Sci., 80: 2026-2030, 1983; and Cole et al., & Cell. Biol., 62: 109-120, 1984). In addition, antibody fragments containing specific binding sites for PKR can be produced. For example, F (ab ') 2 fragments can be prepared by digesting antibody molecules into pepsin, and Fab fragments can be prepared by reducing disulfide bridges of F (ab') 2 fragments, although not limited thereto. Alternatively, the Fab expression library can be miniaturized to quickly and easily identify monoclonal Fab fragments with the desired specificity (Huse WD et al., Science 254: 1275-1281, 1989). The antibody may be bound to a solid substrate to facilitate subsequent steps such as washing or separation of the complex. Solid substrates include, for example, synthetic resins, nitrocellulose, glass substrates, metal substrates, glass fibers, microspheres and micro beads. The synthetic resin includes polyester, polyvinyl chloride, polystyrene, polypropylene, PVDF, and nylon.

The term " treatment " as used herein refers to any action that alters or alleviates Alzheimer ' s disease or symptoms thereof as a result of administration of the composition of the present invention. Those skilled in the art will be able to ascertain the precise criteria of the disease for which the composition of the present invention is effective by referring to the data presented by the Korean Medical Association, will be.

In one embodiment, the pharmaceutical composition may be one or more formulations selected from the group comprising oral formulations, external preparations, suppositories, sterile injectable solutions and sprays.

The therapeutically effective amount of the composition of the present invention may vary depending on a variety of factors, such as the method of administration, the site of administration, the condition of the patient, and the like. Therefore, when used in the human body, the dosage should be determined in consideration of safety and efficacy. It is also possible to estimate the amount used in humans from the effective amount determined through animal experiments. Such considerations in determining the effective amount are described, for example, in Hardman and Limbird, eds., Goodman and Gilman ' s Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; And E.W. Martin ed., Remington ' s Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.

Compositions of the present invention may also include carriers, diluents, excipients, or a combination of two or more thereof commonly used in biological formulations. The pharmaceutically acceptable carrier is not particularly limited as long as the composition is suitable for in vivo delivery, for example, Merck Index, 13th ed., Merck & Inc. A buffered saline solution, a buffer solution, a dextrose solution, a maltodextrin solution, glycerol, ethanol, and one or more of these components may be mixed and used, and if necessary, an antioxidant, a buffer, Conventional additives may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into main dosage forms such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets. Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990) in a suitable manner in the art.

The composition of the present invention may further contain one or more active ingredients showing the same or similar functions. The composition of the present invention contains 0.0001 to 10% by weight, preferably 0.001 to 1% by weight of the protein, based on the total weight of the composition.

The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, Wherein the starch is selected from the group consisting of lactose, mannitol, sugar, arabic gum, pregelatinized starch, cornstarch, powdered cellulose, hydroxypropyl cellulose, opaques, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, Calcium, white sugar, dextrose, sorbitol and talc may be used. The pharmaceutically acceptable additives according to the present invention are preferably included in the composition in an amount of 0.1 to 90 parts by weight, but are not limited thereto.

The composition of the present invention may be administered orally or non-orally (for example, intravenously, subcutaneously, intraperitoneally or topically) or orally administered in accordance with a desired method, and the dose may be appropriately determined depending on the patient's body weight, The range varies depending on diet, time of administration, method of administration, excretion rate, and severity of the disease. The daily dose of the composition according to the present invention is 0.0001 to 10 mg / ml, preferably 0.0001 to 5 mg / ml, more preferably one to several times a day.

Examples of the liquid preparation for oral administration of the composition of the present invention include suspensions, solutions, emulsions, syrups, and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, Etc. may be included together. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.

The present invention will be described in more detail with reference to the following examples. However, the following examples are only for the purpose of illustrating the present invention, and thus the present invention is not limited thereto.

Example 1. Production of Alzheimer's Disease Model

1-1. Aβ _1-42  Accumulation Mouse Model

Aβ _1-42 peptide was dissolved in 1 ml of hexafluoroisopropanol (HFIP, Sigma) at room temperature for 24 hours, and then HFIP was evaporated using nitrogen gas. The dried Aβ _1-42 pellet was dissolved in DMSO (final concentration, 4.4 mM, Duchefa, D1370), immediately frozen and stored at -80 ° C. Adjusted by diluting, Aβ _1-42 Stark to induce oligomerization in DPBS (WELGENE, LB001-02) a final DMSO concentration of 10% was incubated at 37 ℃ for 24 hours. Oligomer A? _1-42 was identified via Western blot (Fig. 1).

The mice were anesthetized (3 mg / kg of Aβ _1-42 oligomer prepared above) using Hamilton syringe (26 gauge) and ketamine 133 mg / kg and xylazine 10.5 mg / kg PBS mixture (ICV, AP = -0.1 mm, ML = +1.0 mm from bregma, DV = -2.6 mm from skull) were injected into the ventricles of the mice. Thereafter, the _mixture was allowed to stand for 5 minutes after the injection for the diffusion of A? _1-42 .

1-2. 5XFAD (5X FAMILY AD) Transgenic Mouse Model

B6SJL-Tg # (APPSwFlLon, PSEN1 * M146L * L286V) A pair of 6799Vas / Mmjax mice (5XFAD) was received by Dr. Song Wook (GIST, Korea). The mice were fed a light-arm cycle for 12 hours. Mice were assigned to groups of 4 to 6 per group and adapted to animal feeding at least a week prior to the experiment. Also, mice were individually maintained for 5 minutes for 4 days in the laboratory before the experiment. 5XFAD mice exhibit Aβ accumulation at 2 months after birth and memory and LTP defects at 6 months (Kimura and Ohno, 2009; Oakley et al., 2006).

Example 2. Confirmation of PKR inhibitor's memory-deficient recovery

We used a novel object recognition (NOR) method (Antunes and Biala, 2012) that is used as an AD-related memory deficiency test in mice to determine whether PKR inhibition affects Aβ _1-42 -dicted memory deficits. Specifically, the NOR task was learned two days after 10-11 month old 5XFAD mouse and the Aβ _1-42 accumulation mouse model in Example 1-1, and the long-term memory memory was tested after 24 hours. Here, PKR inhibitors (PKRi, C-16, 0.335 mg / kg) were treated by intraperitoneal injection 20 minutes before the NOR learning to confirm that the A? _1-42 -induced memory deficits were improved by PKR inhibition.

As a result, 5XFAD mice did not show a significant difference due to the treatment of PKR inhibitors. Also, instead of Aβ _1-42 was significantly the long-term memory of the NOR mice significantly improved because of the NOR memory deficits in the aspect shown Aβ _1-42 accumulation mouse model to the process of the PKR inhibitor as compared to control mice injected with vehicle (FIG. 2 Two-way ANOVA: Interaction of Aβ with PKRi, F (1, 10), and PKRi (vehicle: 61.33 ± 2.86%, PKRi: 60.92 ± 0.84%, Aβ: 49.09 ± 3.21%, Aβ and PKRi: 62.7 ± 2.797% = 9.067, * p <0.0, Bonferroni post-tests: * p <0.05, ** p <0.01, n = 6 per group). This suggests that PKR inhibition may improve long-term memory deficits by accumulating A [beta] _1-42 .

Example 3. Aβ in hippocampus _1-42 - Confirmation of long-term synergistic deficiency recovery induced by induction

Is considered a cellular mechanism for long-term storage, the PKR in order to determine the impact on the long-term cost synergies Bar (Long-term potentiation, LTP) deficiencies reported in the AD mouse model, that is, induced by Aβ _1-42 The LTP in the hippocampal Schaffer-collateral pathway was confirmed by the method of field excitatory postsynaptic potentials (fEPSPs) to determine whether LTP deficiency could be restored by PKRi. Specifically, a 400 μm thick sagittal hippocampus slice was applied to artificial cerebrospinal fluid (ACSF: 120Mm NaCl, 3.5Mm KCl , 2.5Mm CaCl, 1.3Mm MgSO 4, 1.25Mm NaH 2 PO 4, 10Mm D-glucose, 20Mm NaHCO 3) of 500 nM after incubation for one hour at a chamber filled Aβ _{1 -42} were incubated for a further 2 hours at a treatment chamber filled with ACSF. then, PKRi (1μM, 0.002% DMSO )) (Calbiochem, Merck Millipore, Billerica, MA) to the ACSF LTP induction 30 minutes ago dissolved, LTP induction 30 minutes again It was perfused through after 50 minutes. fEPSP was recorded on CA1 striatum radiatum with platinum-iridium electrodes. Bipolar platinum-stimulated electrodes were placed in Schaffer-collaterals, and LTP was stimulated twice with high frequency stimulation (2X HFS; 100 Hz to 100 pulses at 30 Hz intervals) or 3X seta burst stimulation (TBS; 4 pulses at 100 Hz repeated with 200 ms inter-burst intervals protocol. We also compared the mean fEPSP slope after 40-50 min or after 50-60 min of LTP induction to determine if the size of LTP was significantly different between the groups. Data were collected and analyzed using WinLTP (WinLTP Ltd., ver 2.20b).

As a result, Aβ _1-42 -treated hippocampal slices exhibited impaired LTP as compared to vehicle-treated control slices, and thus LTP reduced by Aβ _1-42 was significantly enhanced by PKRi treatment (Vehicle: 143.52 ± 5.22%, n = 7 slices from 6 mice, PKRi: 144.48 ± 9.73%, n = 7 slices from 5 mice, Aβ1-42: 118.00 ± 2.99%, n = 12 slices from 8 mice, Aβ _1-42 and PKRi: 146.28 ± 9.45%, n = 7 slices from 7 mice, interaction of two-way ANOVA, Aβ _1-42 and PKR, F (1, 23) = 4.213, * p <0.05 ; Bonferroni post-tests, * p <0.05, ** p <0.01).

Example 4. Confirmation of the effect of contextual fear memory deficiency recovery in 5XFAD mice

To determine whether PKR inhibition generally improves synaptic plasticity and memory in AD mouse models, regardless of their respective pathogenesis, the effect of PKRi treatment on 5XFAD mice overexpressing human mutant forms of APP and PS1 was assessed by contextual panic conditioning (CFC) (Frankland et al., 1998; Holland and Bouton, 1999; Phillips and LeDoux, 1992). Specifically, 5XFAD mice or general control mice aged 11-12 months were acclimated for 1 hour in the laboratory before fear conditioning study. The mice were then placed in a fear conditioning chamber (Coulbourn Instruments) for 2 minutes, followed by two pairs of a tone (2800 Hz, 85 dB, 30 s) and co-terminating electric foot- 2 s) was added. However, PKR inhibitor (PKRi, C-16, 0.335 mg / kg) was treated by intraperitoneal injection 20 minutes before the study. One day after the training, the chamber was placed in the chamber for 3 minutes to check the fear memory of the mouse's condition. Freezing behavior due to fear was measured with Freeze Frame software (ActiMetrics, IL, USA), and data larger than twice the standard deviation was excluded from the analysis.

As a result, 5XFAD transgenic mice showed a lack of contextual fear memory after 24 hours of learning, but they were able to restore the contextual fear memory deficit by enhancing the phasing behavior by PKRi treatment (Fig. 4) (WT : 49.03 ± 6.67%, n = 9 mice, WT with PKRi: 46.78 ± 5.90%, n = 10 mice, 5XFAD: 8.74 ± 4.18%, n = 6 mice, 5XFAD with PKRi: 35.55 ± 10.38% ; Two-way ANOVA, genotype and PKRi interaction, F (1, 29) = 2.19, p = 0.056, Bonferroni post-tests, * p <0.05, ** p <0.01).

Example 5. Confirmation of recovery effect of hippocampus synaptic plasticity in 5XFAD mouse

To determine if PKR inhibitors can restore synaptic plasticity deficit in the 5XFAD mouse model, we examined the effect of PKR on long-term potentiation (LTP) deficiency. Specifically, PKRi (1 μM, 0.002% DMSO) was treated 40 minutes before LTP induction and throughout the recording after LTP induction (TBS: 4 pulses at 100 Hz, 200 ms inter-burst intervals).

As a result, it was confirmed that PKR inhibitor treatment did not affect LTP in wild-type mice but restored TBS-induced LTP deficiency in 5XFAD mice (Fig. 5, upper) (Average fEPSP slope: last 10 min, WT: 147.77 2X mice, 5XFAD and PKRi: 151.67 +/- 11.20%, n = 6 slices from 4 mice, WT and PKRi: 142.83 +/- 3.10%, n = 9 slices from 5 mice, 5XFAD: 126.22 +/- 2.36% %, n = 5 slices from 3 mice, two-way ANOVA, 5XFAD and PKRi interaction: F (1, 23) = 9.997, * p <0.05; Bonferroni post-tests, ** p <0.01). In addition, unlike TBS, the HFS (high frequency stimulation) protocol induced a similar level of LTP to control mice in 5XFAD mice (Figure 5, bottom) (WT: 159.10 ± 10.06%, n = 10 slices from 4 mice , 5XFAD: 161.00 + 11.89%, n = 4 slices from 3 mice, unpaired t-test, p = 0.92).

Claims (7)

A pharmaceutical composition for the treatment of Alzheimer's disease (AD) comprising an effective amount of a double-stranded RNA-activated protein kinase (PKR) inhibitor. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein the PKR inhibitor is a PKR expression or protein activity inhibitor. The pharmaceutical composition for treating Alzheimer's disease according to claim 2, wherein the PKR expression inhibitor is any one selected from the group consisting of antisense nucleotides, siRNA, shRNA, and ribozyme complementarily binding to the mRNA of the PKR gene. The pharmaceutical composition for treating Alzheimer's disease according to claim 2, wherein the PKR protein activity inhibitor is any one selected from the group consisting of a compound, a peptide and an antibody. The pharmaceutical composition for treating Alzheimer's disease according to claim 4, wherein the compound is a compound represented by the following formula (1)
[Chemical Formula 1]

. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein Alzheimer's disease is familial Alzheimer's disease (FAD) caused by Alzheimer's disease or gene mutation by accumulation of A [beta] _1-42 . The pharmaceutical composition according to claim 1, wherein the Alzheimer's disease is Alzheimer's dementia, memory deficit, synaptic plasticity deficiency, long-term potentiation deficiency or memory deficit disorder.

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