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

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 (2012) Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer’s disease. Aging Cell, 11 4: 559-568. doi:10.1111/j.1474-9726.2012.00817.x


Author 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
Title Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer’s disease
Language of Title eng
Journal name Aging Cell   Check publisher's open access policy
Language of Journal Name eng
ISSN 1474-9718
1474-9726
Publication date 2012
Sub-type Article (original research)
DOI 10.1111/j.1474-9726.2012.00817.x
Open Access Status DOI
Volume 11
Issue 4
Start page 559
End page 568
Total pages 32
Place of publication Oxford, United Kingdom
Publisher Wiley-Blackwell Publishing
Collection year 2013
Language eng
Abstract The cause of elevated level of amyloid β-peptide (Aβ42) in common late-onset sporadic (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 AD patients, 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.
Keyword Alzheimer’s disease
Oxidative stress
Amyloid
Lipid peroxidation
γ-secretase
Nicastrin
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Accepted Article (Accepted, unedited articles published online for future issues) Article first published online: 9 April 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Biomedical Sciences Publications
 
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Created: Sun, 11 Mar 2012, 12:00:57 EST by Dr Thiruma V Arumugam on behalf of School of Biomedical Sciences