title: Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease.
abstract: Beta-secretase (BACE1), an enzyme responsible for the production of amyloid beta-peptide (Abeta), 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 (gamma-secretase)-deficient cells and in normal cells treated with gamma-secretase inhibitors. Oxidative stress-induced beta-secretase activity and sAPPbeta levels were suppressed by gamma-secretase inhibitors. Levels of gamma- and beta-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 gamma-secretase inhibitor. Our findings suggest that gamma-secretase mediates oxidative stress-induced expression of BACE1 resulting in excessive Abeta production in AD.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Woo
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mughal
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Hyun
authors.forename: Jun-Hyung
authors.initials: JH
authors.lastname: Park
authors.forename: Yun-Hyung
authors.initials: YH
authors.lastname: Choi
authors.forename: A-Ryeong
authors.initials: AR
authors.lastname: Gwon
authors.forename: Simonetta
authors.initials: S
authors.lastname: Camandola
authors.forename: Aiwu
authors.initials: A
authors.lastname: Cheng
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
authors.forename: William R
authors.initials: WR
authors.lastname: Markesbery
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000820:Animal Diseases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D001921:Brain / Q000201:enzymology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics
chemical_list: D000447:Aldehydes; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D016877:Oxidants; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C462359:tert-4-hydroxy-2-nonenal; D006861:Hydrogen Peroxide; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human