Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease
Journal
Aging Cell
Journal Volume
11
Journal Issue
4
Pages
559-568
Date Issued
2012
Author(s)
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.
Hyun D.-H.
Cheng A.
Dann C.E.
Bernier M.
Lee J.
Markesbery W.R.
Mattson M.P.
Jo D.-G.
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.
SDGs
Other Subjects
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
Type
journal article