Document Detail

Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease.
MedLine Citation:
PMID:  22404891     Owner:  NLM     Status:  MEDLINE    
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.
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
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2012-04-09
Journal Detail:
Title:  Aging cell     Volume:  11     ISSN:  1474-9726     ISO Abbreviation:  Aging Cell     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-18     Completed Date:  2012-11-13     Revised Date:  2014-11-05    
Medline Journal Info:
Nlm Unique ID:  101130839     Medline TA:  Aging Cell     Country:  England    
Other Details:
Languages:  eng     Pagination:  559-68     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
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MeSH Terms
Aldehydes / chemistry,  metabolism
Alzheimer Disease / metabolism*
Amyloid Precursor Protein Secretases / chemistry,  metabolism*
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / chemistry,  metabolism
Amyloidogenic Proteins / metabolism*
Brain / metabolism
Cell Line
Disease Models, Animal
Lipid Peroxidation
Membrane Glycoproteins / chemistry*,  metabolism*
Membrane Lipids / chemistry,  metabolism
Membrane Microdomains / metabolism
Mice, Transgenic
Neurons / metabolism
Peptide Fragments / metabolism
Protein Structure, Tertiary
Grant Support
Reg. No./Substance:
0/Aldehydes; 0/Amyloid beta-Peptides; 0/Amyloid beta-Protein Precursor; 0/Amyloidogenic Proteins; 0/Membrane Glycoproteins; 0/Membrane Lipids; 0/Peptide Fragments; 0/amyloid beta-protein (1-40); 0/amyloid beta-protein (1-42); 0/nicastrin protein; 29343-52-0/4-hydroxy-2-nonenal; EC 3.4.-/Amyloid Precursor Protein Secretases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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