Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease.
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.
Jo
Dong-Gyu
DG
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
Arumugam
Thiruma V
TV
Woo
Ha-Na
HN
Park
Jong-Sung
JS
Tang
Sung-Chun
SC
Mughal
Mohamed
M
Hyun
Dong-Hoon
DH
Park
Jun-Hyung
JH
Choi
Yun-Hyung
YH
Gwon
A-Ryeong
AR
Camandola
Simonetta
S
Cheng
Aiwu
A
Cai
Huaibin
H
Song
Weihong
W
Markesbery
William R
WR
Mattson
Mark P
MP
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
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