Evidence that γ-secretase mediates oxidative stress-induced β-secretase expression in Alzheimer's disease
Journal
Neurobiology of Aging
Journal Volume
31
Journal Issue
6
Pages
917-925
Date Issued
2010
Author(s)
Jo D.-G.
Arumugam T.V.
Woo H.-N.
Park J.-S.
Mughal M.
Hyun D.-H.
Park J.-H.
Choi Y.-H.
Gwon A.-R.
Camandola S.
Cheng A.
Cai H.
Song W.
Markesbery W.R.
Mattson M.P.
Abstract
β-Secretase (BACE1), an enzyme responsible for the production of amyloid β-peptide (Aβ), is increased by oxidative stress and is elevated in the brains of patients with sporadic Alzheimer's disease (AD). Here, we show that oxidative stress fails to induce BACE1 expression in presenilin-1 (γ-secretase)-deficient cells and in normal cells treated with γ-secretase inhibitors. Oxidative stress-induced β-secretase activity and sAPPβ levels were suppressed by γ-secretase inhibitors. Levels of γ- and β-secretase activities were greater in brain tissue samples from AD patients compared to non-demented control subjects, and the elevated BACE1 level in the brains of 3xTgAD mice was reduced by treatment with a γ-secretase inhibitor. Our findings suggest that γ-secretase mediates oxidative stress-induced expression of BACE1 resulting in excessive Aβ production in AD. ? 2008.
SDGs
Other Subjects
amyloid beta protein; amyloid precursor protein; beta secretase; gamma secretase; gamma secretase inhibitor; presenilin 1; Alzheimer disease; animal cell; animal tissue; article; brain tissue; controlled study; enzyme activity; human; human cell; human tissue; nonhuman; oxidative stress; pathogenesis; priority journal; protein expression; rat; Aldehydes; Alzheimer Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animal Diseases; Animals; Aspartic Acid Endopeptidases; Brain; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Hydrogen Peroxide; Mice; Mice, Transgenic; Mutation; Neuroblastoma; Oxidants; Oxidative Stress; Peptide Fragments; Presenilin-1; Presenilin-2; RNA, Messenger; RNA, Small Interfering; tau Proteins
Type
journal article