Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease

A. Ryeong Gwon, Jong Sung Park, Thiruma V. Arumugam, Yong Kook Kwon, Sic L. Chan, Seol Hee Kim, Sang Ha Baik, Sunghee Yang, Young Kwang Yun, Yuri Choi, Saerom Kim, Sung Chun Tang, Dong Hoon Hyun, Aiwu Cheng, Charles E. Dann, Michel Bernier, Jaewon Lee, William R. Markesbery, Mark P. Mattson, Dong Gyu Jo

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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.

Original languageEnglish
Pages (from-to)559-568
Number of pages10
JournalAging Cell
Issue number4
StatePublished - Aug 2012


  • Alzheimer's disease
  • Amyloid
  • Lipid peroxidation
  • Nicastrin
  • Oxidative stress
  • γ-secretase


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