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Gwon, A‐,Ryeong,Park, Jong‐,Sung,Arumugam, Thiruma V.,Kwon, Yong‐,Kook,Chan, Sic L.,Kim, Seol‐,Hee,Baik, Sang‐,Ha,Yang, Sunghee,Yun, Young‐,Kwang,Choi, Yuri,Kim, Sa Blackwell Publishing Ltd 2012 AGING CELL Vol.11 No.4
<P><B>Summary</B></P><P>The cause of elevated level of amyloid β‐peptide (Aβ42) in common late‐onset sporadic [Alzheimer’s disease (AD)] has not been established. Here, we show that the membrane lipid peroxidation product 4‐hydroxynonenal (HNE) is associated with amyloid and neurodegenerative pathologies in AD and that it enhances γ‐secretase activity and Aβ42 production in neurons. The γ‐secretase substrate receptor, nicastrin, was found to be modified by HNE in cultured neurons and in brain specimens from patients with AD, in which HNE–nicastrin levels were found to be correlated with increased γ‐secretase activity and Aβ plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the γ‐secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of γ‐secretase activity and Aβ42 production by HNE were blocked by an HNE‐scavenging histidine analog in a 3xTgAD mouse model of AD. These findings suggest a specific molecular mechanism by which oxidative stress increases Aβ42 production in AD and identify HNE as a novel therapeutic target upstream of the γ‐secretase cleavage of APP.</P>
Effects of chronic alcohol consumption on expression Levels of APP and Aβ-producing enzymes
( Sae Rom Kim ),( Hye Young Jeong ),( Sung Hee Yang ),( Sung Pil Choi ),( Min Young Seo ),( Young Kwang Yun ),( Yuri Choi ),( Sang Ha Baik ),( Jong Sung Park ),( A Ryeong Gwon ),( Dong Kwon Yang ),( C 생화학분자생물학회(구 한국생화학분자생물학회) 2011 BMB Reports Vol.44 No.2
Chronic alcohol consumption contributes to numerous diseases, including cancers, cardiovascular diseases, and liver cirrhosis. Epidemiological studies have shown that excessive alcohol consumption is a risk factor for dementia. Along this line, Alzheimer`s disease (AD) is the most common form of dementia and is caused by the accumulation of amyloid-β (Aβ plaques in neurons. In this study, we hypothesized that chronic ethanol consumption is associated with pathological processing of APP in AD. To investigate the relationship between chronic alcohol consumption and Aβ production, brain samples from rats fed an alcohol liquid diet for 5 weeks were analyzed. We show that the expression levels of APP, BACE1, and immature nicastrin were increased in the cerebellum, hippocampus, and striatum of the alcohol-fed group compared to the control group. Total nicastrin and PS1 levels were induced in the hippocampus of alcohol-fed rats. These data suggest that the altered expression of APP and Aβ-producing enzymes possibly contributes to the chronic alcohol consumption-mediated pathogenesis of AD. [BMB reports 2011; 44(2): 135-139]