1. Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease.
- Author
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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, Saerom, Tang, Sung-Chun, Hyun, Dong-Hoon, Cheng, Aiwu, Dann, Charles E., Bernier, Michel, Lee, Jaewon, Markesbery, William R., Mattson, Mark P., and Jo, Dong-Gyu
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OXIDATION ,NICASTRIN ,LIPID peroxidation (Biology) ,ALZHEIMER'S disease ,SECRETASES ,OXIDATIVE stress ,AMYLOID - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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