Open AccessOxidative lipid modification of nicastrin enhances amyloidogenic γ‐secretase activity in Alzheimer’s disease
Author(s) -
Gwon ARyeong,
Park JongSung,
Arumugam Thiruma V.,
Kwon YongKook,
Chan Sic L.,
Kim SeolHee,
Baik SangHa,
Yang Sunghee,
Yun YoungKwang,
Choi Yuri,
Kim Saerom,
Tang SungChun,
Hyun DongHoon,
Cheng Aiwu,
Dann Charles E.,
Bernier Michel,
Lee Jaewon,
Markesbery William R.,
Mattson Mark P.,
Jo DongGyu
Publication year - 2012
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2012.00817.x
Subject(s) - nicastrin , presenilin , oxidative stress , lipid peroxidation , amyloid precursor protein , alzheimer's disease , amyloid precursor protein secretase , biochemistry , 4 hydroxynonenal , biology , pharmacology , microbiology and biotechnology , chemistry , medicine , disease
Summary 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.