https://scholars.lib.ntu.edu.tw/handle/123456789/519390
標題: | Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease | 作者: | 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. SUNG-CHUN TANG Hyun D.-H. Cheng A. Dann C.E. Bernier M. Lee J. Markesbery W.R. Mattson M.P. Jo D.-G. |
公開日期: | 2012 | 卷: | 11 | 期: | 4 | 起(迄)頁: | 559-568 | 來源出版物: | Aging Cell | 摘要: | 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. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84864012821&doi=10.1111%2fj.1474-9726.2012.00817.x&partnerID=40&md5=151631876daec11df5ae6603a75115aa https://scholars.lib.ntu.edu.tw/handle/123456789/519390 |
ISSN: | 1474-9718 | DOI: | 10.1111/j.1474-9726.2012.00817.x | SDG/關鍵字: | 4 hydroxynonenal; amyloid beta protein[1-40]; amyloid beta protein[1-42]; amyloid precursor protein; gamma secretase; histidine derivative; histidyl hydrazide; nicastrin; unclassified drug; Alzheimer disease; animal experiment; animal model; article; controlled study; enzyme activity; human; human cell; lipid peroxidation; lipid raft; male; mouse; nerve cell; nonhuman; oxidative stress; priority journal; protein binding; protein domain; protein modification; Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Amyloidogenic Proteins; Animals; Brain; Cell Line; Disease Models, Animal; Humans; Lipid Peroxidation; Membrane Glycoproteins; Membrane Lipids; Membrane Microdomains; Mice; Mice, Transgenic; Neurons; Peptide Fragments; Protein Structure, Tertiary |
顯示於: | 醫學系 |
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