• 동의생리병리학회지
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• 제18권5호
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• pp.1418-1425
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• 2004

The water extract of Chongmyung-tang has been traditionally used for treatment of memory-disorder in oriental medicine. This study was designed to investigate the protective mechanisms of Chongmyung-tang on β-amyloid or H₂O₂-induced cytotoxicity in Neuro 2A cells. The water extract of Chongmyung-tang significantly reduced both β-amyloid or H₂O₂-induced cell death and apoptotic characteristics through reduction of intracellular peroxide generation. Also, it inhibited the mitochondrial dysfunction including the disruption of mitochondria membrane permeability transition(MPT) and the modulation in expression of Bcl-2 family proteins in H₂O₂-treated H9c2 cells. Furthermore, pretreatment of quercetin inhibited the activation of caspase-3, in turn, degradation of ICAD/DFF45 were completely abolished in H₂O₂-treated cells. Taken together, that data suggest that the protective effects of the water extract of Chongmyung-tang against β-amyloid induced oxidative injuries may be achieved through modulation of mitochondrial dysfunction.

• 약학회지
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• 제54권6호
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• pp.529-534
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• 2010

Alzheimer's disease (AD) is characterized pathologically by the presence of intracellular neurofibrillary tangles and deposition of ${\beta}$-amyloid ($A{\beta}$) peptides, which are generated by processing of amyloid precursor protein (APP). It is urgent to develop effective therapies for the treatment of AD, since our society rapidly accelerate aging. $A{\beta}$ peptides have been believed to be neurotoxic and now are also considered to have effects on the mechanism of memory formation. Recently, we investigated that a quinoline compound from natural product reduced the secretion of $A{\beta}$ from the neuroblastoma N2a cells (NL/N cell line) overexpressing APPswe. In this study, 3-phenyl-1-isoquinolinamine, a synthetic isoquinoline compound was analyzed to determine its effects on the metabolism of APP. It inhibited the secretion of $A{\beta}$ peptides from the N2a NL/N cell line. Beta-site APP cleaving enzyme (BACE) fluorescence resonance energy transfer (FRET) assay revealed that it inhibited BACE activity in a dose dependent manner. Immunoblotting study showed that it inhibited APP stabilization and expression and it slightly increased the stablization and the expression of ${\gamma}$-secreatase component from the N2a NL/N cell line. We suggest that 3-phenyl-1-isoquinolinamine inhibits APP metabolism and $A{\beta}$ generation by the means of BACE inhibitory mechanism. This is the first report that 3-phenyl-1-isoquinolinamine inhibits the secretion of $A{\beta}$ peptides from neuroblastoma cells.

• 생명과학회지
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• 제17권1호
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• pp.18-23
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• 2007

신경세포에 특이적으로 발현되는 단백질인 Fe65는 두 개의 phosphotyrosine binding(PTB) 도메인을 가지고 있다. 두번째 PTB(PTB2)도메인은 아밀로이드 베타 전구 단백질(APP)의 세포질 도메인 조각(AICD)와 결합한다. 최근 연구 결과들은 AICD와 Fe65로 이루어진 결합체가 알츠하이머병에서 신경세포를 죽게 하는 유전자를 발현한다고 제시하고 있다. 따라서 Fe65와 AICD의 결합을 방해하는 화합물은 알츠하이머병을 치료하는데 후보물질이 될 수 있다. 하지만 AICD와 Fe65와 관련된 신호전달에 대한 분자적 기전은 잘 알려져 있지 않다. 이번 연구에서는 Fe65의 PTB2도메인을 baculovirus시스템에서 과발현시킨 결과를 보고한다. 세균 및 척추동물 세포를 이용한 시스템과 비교했을 때, baculovirus 시스템 이 훨씬 효과적 이 다는 것을 발견했다. 정제된 재조합 단백질을 이용하여 초기 결정을 얻었다. 결정을 이용하여 앞으로 밝힐 3차원 구조는 Fe65관련 신호전달체계에 대한 분자 기전 및 이에 대한 저해제 개발에 큰 도움을 줄 것이다.

• 약학회지
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• 제56권5호
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• pp.293-298
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• 2012

The present study tested the effect of Schizandra chinensis lignan compounds, Gomisin A and Schizandrin, on the aggregation and dissociation of beta-amyloid $(A{\beta})_{1-42}$ to explore a possible therapeutic target for Alzheimer's disease. Gomisin A significantly inhibited the $A{\beta}_{1-42}$ aggregation in a dose dependent manner, but did not induced the dissociation of aggregated $A{\beta}_{1-42}$. On the other hand, Schizandrin significantly suppressed the aggregation and dissociation of $A{\beta}_{1-42}$. These results suggest that Gomisin A and Schizandrin, which are known as biologically active ingredients from Schizandra chinensis, may be potentially useful target molecules to develop a drug for the prevention or treatment of Alzheimer's disease.

• 동의신경정신과학회지
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• 제30권4호
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• pp.327-340
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• 2019

Objectives: Alzheimer's disease (AD) is a complex disease accompanied by slow impairment of memory and coordination leading to behavioral changes. To date, the only treatment option is to delay the progress of the disease. The purpose of this study was to investigate the synergistic effects of combination treatment with donepezil and three herbal extracts SIP-3 in the AD mouse model induced by amyloid-β (Aβ). Methods: We tested SIP-3 extracts for the cytotoxicity on Aβ-treated SH-SY5Y cells. Then the synergistic effects of SIP-3 and donepezil were evaluated in the AD mouse model using animal experiments and the next generation sequencing (NGS) study. Results: We found that co-treatment with SIP-3 extracts and donepezil increased the viability in Aβ-treated SH-SY5Y cells. The beneficial effects of the co-treatment were also observed in the Aβ-induced AD mouse model. The NGS study was performed to show that the co-treatment of SIP-3 and donepezil restored the disease phenotype closely to the normal level in the AD mouse model in terms of mRNA expression. However, the phenotypes were only partially restored. Conclusions: This study suggests that the combination treatment has a potential to be used for the treatment of AD. However, longer periods of treatment may be required.

• 공업화학
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• 제32권1호
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• pp.1-9
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• 2021

알츠하이머병은 신경퇴행질환으로 뇌조직에서 발생하는 아밀로이드 베타(amyloid-β, Aβ) 펩타이드의 축적과 응집, 타우 단백질의 초인산화, 고농도의 특정 금속이온 축적에 의해 발병하는 것으로 알려져 있다. 현재까지 효과적인 치료제가 개발되지 못하였기 때문에, 알츠하이머병을 초기에 정확하게 진단하는 기술은 매우 중요하다. 알츠하이머병의 진단을 위해 개발된 다양한 기법 중 형광 프로브를 이용한 알츠하이머병의 바이오마커 영상화는 많은 연구자들의 관심을 받고 있다. 본 리뷰 논문에서는 최근 개발된 알츠하이머병 진단용 형광 프로브의 구조와, 체내 뇌 영상화에의 적용을 소개하고자 한다. 본 논문은 향후 새로운 프로브를 개발하고자 하는 연구자들에게 많은 도움이 될 것으로 기대된다.

• 대한본초학회지
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• 제34권3호
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• pp.1-7
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• 2019

Objectives : Amyloid ${\beta}(A{\beta})$ could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). This study was investigated the effect of Angelica keiskei KOIDZUMI (AK) on memory in $A{\beta}$-induced an AD model. Methods : AK was extracted uses 70% ethanol solvent. Total polyphenol and flavonoids content were obtained by the Folin-Ciocalteu and the Ethylene glycol colorimetric methods, respectively. The antioxidant activities were assessed through free radical scavenging assays using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazolin-6-sulfonic acid) (ABTS) methods. Intracerebroventrical (i.c.v) injection of $A{\beta}$ 1-42 was used to induce AD in male ICR mice, followed by administrations of 5, 10 or 20 mg/kg AK on a daily. Animals were subjected to short and long term memory behavior in Y-maze and passive avoidance test. Results : The total polyphenol and flavonoids contents of the AK extract were $88.73{\pm}6.36mg$ gallic acid equivalent/g, $84.21{\pm}5.04mg$ rutin equivalent/g, respectively. The assays of DPPH and ABTS revealed that AK extract in treated concentrations (31.25, 62.5, 125, 250, 500, $1000{\mu}g/m{\ell}$) increased antioxidant activity in a dose-dependent manner. Oral administration of AK extract significantly reversed the $A{\beta}$ 1-42-induced decreasing of the spontaneous alternation in the Y-maze test and $A{\beta}$ 1-42-induced shorting of the step-through latency in the passive avoidance test. Conclusions : The findings suggest that AK indicated the antioxidant protective effects against $A{\beta}$-induced memory deficits, and therefore a potential lead natural therapeutic drug or agent for AD.

• 노인정신의학
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• 제16권1호
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• pp.17-23
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• 2012

The diagnosis of Alzheimer's disease (AD) is still obscure even to specialists. To improve the diagnostic accuracy, to find at-risk people as early as possible, to predict the efficacy or adverse reactions of pharmacotherapy on an individual basis, to attain more reliable results of clinical trials by recruiting better defined participants, to prove the disease-modifying ability of new candidate drugs, to establish prognosis-based therapeutic plans, and to do more, is now increasing the need for biomarkers for AD. Among AD-related biochemical markers, cerebrospinal beta-amyloid and tau have been paid the most attention since they are materials directly interfacing the brain interstitium and can be obtained through the lumbar puncture. Level of beta-amyloid is reduced whereas tau is increased in cerebrospinal fluid of AD patients relative to cognitively normal elderly people. Remarkably, such information has been found to help predict AD conversion of mild cognitive impairment. Despite inconsistent findings from previous studies, plasma beta-amyloid is thought to be increased before the disease onset, but show decreasing change as the disease progress. Regarding other peripheral biochemical markers, omics tools are being widely used not only to find useful biomarkers but also to generate novel hypotheses for AD pathogenesis and to lead new personalized future medicine.

• 대한영상의학회지
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• 제83권3호
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• pp.486-507
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• 2022

뇌소혈관질환은 뇌 자기공명영상에서 흔히 관찰되는 혈관성 변화로 뇌백질 고신호강도, 뇌미세출혈, 열공성 경색, 혈관주위공간 등을 포함한다. 이러한 혈관성 변화가 알츠하이머병(Alzheimer's disease; 이하 AD)의 발병 및 진행과 관련되어 있고, 대표 병리인 베타 아밀로이드 및 타우 단백의 침착과도 연관되어 있다는 증거들이 축적되고 있다. 혈관성 변화는 생활습관 개선이나 약물 치료를 통해 예방과 개선이 가능하기 때문에 뇌소혈관질환과 AD 및 AD 생체지표의 관련성을 연구하는 것이 중요하다. 본 종설에서는 AD와 AD 생체지표에 대해 간략히 소개하고, AD와 혈관성 변화의 관련성에 대해 축적된 증거들을 제시한 다음, 뇌소혈관질환의 병태 생리와 MR 영상 소견을 설명하고자 한다. 또 뇌소혈관질환과 AD 진단의 위험도 및 AD 생체지표와의 관련성에 대한 기존 연구 결과들을 정리하고자 한다.

• 약학회지
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• 제50권5호
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• pp.326-331
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• 2006

We designed and synthesized new benzylpiperidinyl ether derivatives as beta-amyloid aggregation inhibitors for the development of novel anti-Alzheimer's disease agents. As starting material, 4-hydroxypiperidine was used. For protection of the amine group in piperidine (2), di-tert-butyl dicarbonate was reacted with 4-hydroxypiperidine in the presence of triethylamine. For introduction of benzyl group, benzylbromide was treated with compound 2 in dioxane. After deprotection of Boc group on amine in compound 3, ester (5) was synthesized by addition of ethyl-4-chlorobutyrate. The alcohol 6 was synthesized by hydride reduction of 5 using $LiAlH_4$. To obtain final products (7-14), the alcohol 6 was condensed with each of substituted benzoic acids. To screen beta-amyloid aggregation inhibition of the products, thioflavinT assay was performed using $A{\beta}1-42\;at\;37^{\circ}C$ for 26 h incubation, in vitro. From the result of screening, compound 8, 9, 11 and 12 showed effective activity about $65{\sim}85\;{\mu}M\;as\;IC_{50}$ value. Among the prepared compounds, 4-[4-(benzyloxy)piperidino]butyl-4-chlorobenzoate (8) was the most effective inhibitor having $IC_{50}\;of\;65.4{\mu}M$.