• EDISON SW 활용 경진대회 논문집
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• 제3회(2014년)
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• pp.237-249
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• 2014

Deposition of amyloid-${\beta}$ ($A{\beta}$) proteins is the conventional pathological hallmark of Alzheimer's disease (AD). The $A{\beta}$ protein formed from the amyloid precursor protein is predominated by the 40 residue protein ($A{\beta}40$) and by the 42 residue protein ($A{\beta}42$). While $A{\beta}40$ and $A{\beta}42$ differ in only two amino acid residues at the C-terminal end, $A{\beta}42$ is much more prone to aggregate and exhibits more neurotoxicity than $A{\beta}40$. Here, we investigate the molecular origin of the difference in the aggregation propensity of these two proteins by performing fully atomistic, explicit-water molecular dynamics simulations. Then, it is followed by the solvation thermodynamic analysis based on the integral-equation theory of liquids. We find that $A{\beta}42$ displays higher tendency to adopt ${\beta}$-sheet conformations than $A{\beta}40$, which would consequently facilitate the conversion to the ${\beta}$-sheet rich fibril structure. Furthermore, the solvation thermodynamic analysis on the simulated protein conformations indicates that $A{\beta}42$ is more hydrophobic than $A{\beta}40$, implying that the surrounding water imparts a larger thermodynamic driving force for the self-assembly of $A{\beta}42$. Taken together, our results provide structural and thermodynamic grounds on why $A{\beta}42$ is more aggregation-prone than $A{\beta}40$ in aqueous environments.

• Journal of Acupuncture Research
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• 제20권4호
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• pp.145-156
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• 2003

Objective : This study is to investigate the effect of electro-acupuncture ST36 on altered transmission of afferent somatosensory information caused by amyloid-${\beta}$(A-${\beta}$) that caused Alzheimer's disease. Methods : The effects of topical application of A-${\beta}$, A-${\beta}$ with ST36, aggregated A-${\beta}$(aA-${\beta}$), aA-${\beta}$ with ST36 and ST36 on the afferent sensory transmission to the neurons in the primary somatosensory(SI) cortex was observed in anesthetized rats. Quantitative determination of the effects of A-${\beta}$, A-${\beta}$ with ST36, aA-${\beta}$, aA-${\beta}$ with ST36 and ST36 was made by generating poststimulus time histogram of evoked response of individual cortical neuron by electrical stimulation of the receptive located in peripheral area(forepaw) Results : The results obtained in present study were summerized as follow : 1. Application of physiological concentrative 0.5 nM A-${\beta}$ caused afferent sensory transmission of SI cortex facilitated. 0.5 nM A-${\beta}$ with ST36 exerted much stronger effects than 0.5 nM A-${\beta}$ alone. 2. Application of $10{\mu}M$ A-${\beta}$ caused afferent sensory transmission of SI cortex unchangeable. But $10{\mu}M$ A-${\beta}$ with ST36 is facilitated at 30 min of post-drug period 3. Application of $10{\mu}M$ aA-${\beta}$ caused afferent sensory transmission of SI cortex diminished. $10{\mu}M$ aA-${\beta}$ with ST36 is diminished after 15min of post-drug period but is facilitated after 75min.

• Bulletin of the Korean Chemical Society
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• 제29권8호
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• pp.1505-1509
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• 2008

Comparative molecular simulations were performed to establish molecular interaction and inhibitory effect of flavonoid myricetin on formation of amyloid fibris. For computational comparison, the conformational stability of myricetin with amyloid $\beta$ -peptide (A$\beta$ ) and $\beta$ -amyloid fibrils (fA$\beta$) were traced with multiple molecular dynamics simulations (MD) using the CHARMM program from Monte Carlo docked structures. Simulations showed that the inhibition by myricetin involves binding of the flavonoid to fA$\beta$ rather than A$\beta$ . Even in MD simulations over 5 ns at 300 K, myricetin/fA$\beta$ complex remained stable in compact conformation for multiple trajectories. In contrast, myricetin/A$\beta$ complex mostly turned into the dissociated conformation during the MD simulations at 300 K. These multiple MD simulations provide a theoretical basis for the higher inhibitory effect of myricetin on fibrillogenesis of fA$\beta$ relative to A$\beta$ . Significant binding between myricetin and fA$\beta$ observed from the computational simulations clearly reflects the previous experimental results in which only fA$\beta$ had bound to the myricetin molecules.

• 한국환경성돌연변이발암원학회:학술대회논문집
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• 한국환경성돌연변이발암원학회 2003년도 추계학술대회
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• pp.139-140
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• 2003

• 동의생리병리학회지
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• 제24권1호
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• pp.91-95
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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. 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 affects on the mechanism of memory formation, which are generated by processing of amyloid precursor protein (APP). In this study, effects of Styrax Liquides (SL) on the metabolism of APP were analyzed. SL inhibited the secretion of A${\beta}$ from the Neuro2a cell line (APPswe cell) expressing a mutation of APPswe. Immunoblotting study showed that it inhibited ${\beta}$-site APP cleaving enzyme (BACE) from the APPswe cells. We suggest that SL inhibits APP metabolism and A${\beta}$ generation by the means of BACE inhibitory mechanism. This is the first report that SL inhibits the secretion of A${\beta}$ peptides from neuroblastoma cells.

• Animal cells and systems
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• 제5권2호
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• pp.139-143
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• 2001

Alzheimer's disease is the most common form of dementia and no cure is known so far. Extensive genetic works and in vitro experiments combined with clinical observations link amyloid $\beta$--protein (A$\beta$-) to the pathogenesis of Alzheimer's disease (AD). It was hypothesized that $A\beta$- becomes toxic when it adopts a fibrillar conformation. Recently, non-fibrillar form of $A\beta$- was observed and the potential role in the pathogenesis of AD became an interesting subject. In this study, the cytotoxicity of non-fibrillar $A\beta$- and fibrillar $A\beta$- was compared on oxidative stress, membrane damage, or nucleosome break down. Non-fibrillar $A\beta$- was not toxic in peripheral nervous system-derived cells but significantly toxic in central nervous system-derived cells while fibrillar $A\beta$- was non-selectively toxic in both cell culture. The neurotoxicity of non-fibrillar $A\beta$- was reproduced in semi-in vivo culture of mouse brain slice. In conclusion, non-fibrillar $A\beta$- could be more relevant to the selective neurodegeneration in Alzheimer's brains than fibrillar $A\beta$- and further research needs to be done for identification of the cause of AD.

• BMB Reports
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• 제43권6호
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• pp.413-418
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• 2010

Beta-Amyloid ($A{\beta}$)-induced neuroinflammation is one of the key events in the development of neurodegenerative disease. We previously reported that KHG21834, a benzothiazole derivative, attenuates $A{\beta}$-induced degeneration of cortical and mesencephalic neurons in vitro. In the present work, we show that KHG21834 reduces $A{\beta}$-mediated neuroinflammation in brain. In vivo intracerebroventricular infusion of KHG21834 leads to decreases in the numbers of activated astrocytes and microglia and level of proinflammatory cytokines such as interleukin-$1{\beta}$ and tumor necrosis factor-$\alpha$ induced by $A{\beta}$ in the hippocampus. This suppression of neuroinflammation is associated with decreased neuron loss, restoration of synaptic dysfunction biomarkers in the hippocampus to control level, and diminished amyloid deposition. These results may suggest the potential therapeutic efficacy of KHG21834 for the treatment of $A{\beta}$-mediated neuroinflammation.

• 생명과학회지
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• 제15권2호
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• pp.169-175
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• 2005

Resveratrol (3,4',5-trihydroxy-trans-stilbene)은 포도와 같은 식물에서 각종 감염균으로부터 자신의 몸을 보호하기 위하여 생성되는 물질인 phytoalexin의 일종으로 강력한 항산화작용, 암예방 효과 및 항암 작용을 포함한 각종 약리작용을 가진 것으로 보고 되어져 오고 있다. Alzheimer 환자의 뇌에 축적되어 뇌 신경세포를 죽이는 amyloid plaque의 주 성분은 $amyloid-\beta$의 축적에 의한 것인데, $amyloid-\beta$는 정상적인 단백질 신진대사 과정의 결과로 체내 모든 세포들로부터 생성되는 물질이다. 본 연구에서는 resveratrol의 세포독성 보호효과에 관한 효능을 검증하기 위하여 C6 신경교세포에서 $amyloid-\beta-peptide$ (fragment 31-35)에 의한 세포독성 및 세포성장 조절관련 주요 유전자들의 발현에 미치는 resveratrol의 영향을 조사하였다. $Amyloid-\beta$가 처리된 C6세포는 처리 농도의존적으로 증식이 억제되었으며, 형태적 변형도 유발 되었으나 resveratrol의 전처리에 의하여 효과적으로 차단되었다. RT-PCR 및 Western blot analysis에 의한 결과에서 $amyloid-\beta$ 처리에 의한 세포증식 억제는 종양억제유전자 p53 및 Cdk 억제제인 p21 (WAF1/CIP1) 발현이 증가되었다. 또한 apoptosis 유발에 매우 중요한 역할을 수행하는 Bax의 발현도 $amyloid-\beta$가 처리된 C6 세포에서 발현이 증가되었으나 apoptosis 유발억제에 관여하는 Bcl-2및 $Bcl-X_{L}$ 발현에는 큰 영향을 미치지 못하였다. 그러나 resveratrol이 전처리된 세포에서는 처리 농도 의존적으로 $amyloid-\beta$에 의해 유도되는 p53, p21 및 Bax의 발현이 정상수준으로 회복되었다.

• 생약학회지
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• 제46권4호
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• pp.327-333
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• 2015

Alzheimer's disease (AD) is a progressive neurodegenerative disorder symptomatically characterized by impairment in memory and cognitive abilities. AD is characterized pathologically by the deposition of ${\beta}$-amyloid ($A{\beta}$) peptides of 40-42 residues, which are generated by processing of amyloid precursor protein (APP). $A{\beta}$ has been believed to be neurotoxic and now is also considered to have a role on the mechanism of memory dysfunction. In this study, we tested that EtOH extract of the fruits of Chaenomeles sinensis Koehne (CSE) affects on the processing of APP from the APPswe over-expressing Neuro2a cell line. We found that CSE increased over 2 folds of the $sAPP{\alpha}$ secretion level, a metabolite of ${\alpha}$-secretase. We showed that CSE reduced the secretion level of $A{\beta}42$ and $A{\beta}40$ by down regulation of ${\beta}$-secretase (BACE) without cytotoxicity. Furthermore, we found that CSE inhibited BACE and acetylcholinesterase activity in vitro. We suggest that Chaenomelis Fructus may be an useful source to develop a herbal medicine for AD.

• 동의생리병리학회지
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• 제19권1호
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• pp.242-245
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• 2005

The most common feature of neurodegenerative disease (i.e. Alzheimer's disease, AD) is the increased number of activated microglial cells nearby the pathogenic area of the brain, such as amyloid plaque in AD. An abnormality of protein regulation and an imbalance of clearance against ${\beta}-amyloid\;(A{\beta})$ produced amyloid precursor protein (APP) can turn microglia into the activated feature out of the ramified resting phase. We examined the possibility that ginsenoside Rb1 could attenuate the microglial activation induced by massive $A{\beta}$ that has known to induce a chronic inflammation, which is a major cause of AD by damaging neuronal cells (i.e. apoptosis or necrosis). Aggregated $A{\beta}42\;(5\;{\mu}M)$ peptide was used with lipopolysaccharide (LPS) ($10\;{\mu}g$) for a comparative control up to 48hours. We found that Rb1 reduced the production of nitric oxide as well as proinflammatory cytokines, such as $IL-1{\beta}$ and $TNF-{\alpha}$.