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 TANGHyun D.-H.Cheng A.Dann C.E.Bernier M.Lee J.Markesbery W.R.Mattson M.P.Jo D.-G.2020-11-032020-11-0320121474-9718https://www.scopus.com/inward/record.uri?eid=2-s2.0-84864012821&doi=10.1111%2fj.1474-9726.2012.00817.x&partnerID=40&md5=151631876daec11df5ae6603a75115aahttps://scholars.lib.ntu.edu.tw/handle/123456789/519390The 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.[SDGs]SDG34 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, Tertiaryjournal article10.1111/j.1474-9726.2012.00817.x224048912-s2.0-84864012821