Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer’s disease Academic Article uri icon


  • 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.


  • 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
  • Jo, Dong-Gyu

publication date

  • August 2012

has subject area