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

Title
Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease
Authors
Gwon A.-R.Park J.-S.Arumugam T.V.Kwon Y.-K.Chan S.L.Kim S.-H.Baik S.-H.Yang S.Yun Y.-K.Choi Y.Kim S.Tang S.-C.Hyun D.-H.Cheng A.Dann C.E.Bernier M.Lee J.Markesbery W.R.Mattson M.P.Jo D.-G.
Ewha Authors
현동훈
SCOPUS Author ID
현동훈scopus
Issue Date
2012
Journal Title
Aging Cell
ISSN
1474-9718JCR Link
Citation
vol. 11, no. 4, pp. 559 - 568
Indexed
SCIE; SCOPUS WOS scopus
Abstract
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. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
DOI
10.1111/j.1474-9726.2012.00817.x
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자연과학대학 > 생명과학전공 > Journal papers
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