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Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease.
MedLine Citation:
PMID:  22404891     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
Authors:
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 Iii; Michel Bernier; Jaewon Lee; William R Markesbery; Mark P Mattson; Dong-Gyu Jo
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-10
Journal Detail:
Title:  Aging cell     Volume:  -     ISSN:  1474-9726     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101130839     Medline TA:  Aging Cell     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
Affiliation:
School of Pharmacy, Sungkyunkwan University, Korea Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA School of Biomedical Sciences, University of Queensland, Brisbane, Qld, Australia, Laboratory of Clinical investigation, National Institute on Aging Intramural Research Program, Baltimore, MD, USA College of Medicine, University of Central Florida, Orlando, FL 32816, USA. Department of Neurology, National Taiwan University Hospital, Yun-Lin Branch, Taiwan, Division of Life and Pharmaceutical Sciences, Ewha Woman's University, Korea Department of Chemistry, Indiana University, Bloomington, IN, USA College of Pharmacy, Pusan National University, Korea Sanders-Brown Research Center on Aging, University of Kentucky, Lexington, KY, USA Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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