Evidence that γ-secretase mediates oxidative stress-induced β-secretase expression in Alzheimer's disease

被引：81

作者：

Jo, Dong-Gyu ^{[1
,2
]}

Arumugam, Thiruma V. ^{[1
]}

Woo, Ha-Na ^{[2
]}

Park, Jong-Sung ^{[2
]}

Tang, Sung-Chun ^{[1
,3
]}

Mughal, Mohamed ^{[1
]}

Hyun, Dong-Hoon ^{[1
,4
]}

Park, Jun-Hyung ^{[2
]}

Choi, Yun-Hyung ^{[2
]}

Gwon, A-Ryeong ^{[2
]}

Camandola, Simonetta ^{[1
]}

Cheng, Aiwu ^{[1
]}

Cai, Huaibin ^{[5
,6
]}

Song, Weihong ^{[7
]}

Markesbery, William R. ^{[8
]}

Mattson, Mark P. ^{[1
,9
]}

机构：

[1] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA

[2] Sungkyunkwan Univ, Coll Pharm, Suwon, South Korea

[3] Natl Taiwan Univ Hosp, Stroke Ctr, Dept Neurol, Taipei, Taiwan

[4] Ewha Womans Univ, Div Mol Life Sci, Seoul, South Korea

[5] Univ British Columbia, Dept Psychiat, Brain Res Ctr, Vancouver, BC V5Z 1M9, Canada

[6] Univ British Columbia, Grad Program Neurosci, Vancouver, BC V5Z 1M9, Canada

[7] NIA, Neurogenet Lab, Bethesda, MD 20892 USA

[8] Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY USA

[9] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

来源：

NEUROBIOLOGY OF AGING | 2010年 / 31卷 / 06期

关键词：

beta-Secretase; Alzheimer's disease; Oxidative stress; gamma-Secretase; AMYLOID PRECURSOR PROTEIN; DEPENDENT TRANSCRIPTIONAL CONTROL; DEGRADING ENZYME NEPRILYSIN; LIPID-PEROXIDATION; A-BETA; INTRACELLULAR DOMAINS; FREE-RADICALS; BACE1; COMPLEXES; TRANSPORT;

D O I：

10.1016/j.neurobiolaging.2008.07.003

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

B-Secretase (BACE I), an enzyme responsible for the production of amyloid p-peptide (AB), 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 BACE I expression in presenilin-I (gamma-secretase)-deficient cells and in normal cells treated with gamma-secretase inhibitors. Oxidative stress-induced B-secretase activity and sAPPB levels were suppressed by gamma-secretase inhibitors. Levels of and beta-secretase activities were greater in brain tissue samples from AD patients compared to non-demented control subjects, and the elevated BACE I level in the brains of 3xTgAD mice was reduced by treatment with a gamma-secretase inhilitor. Our findings suggest that gamma-secretase mediates oxidative stress-induced expression of BACE I resulting in excessive AB production in AD. Published by Elsevier Inc.

引用

页码：917 / 925

页数：9

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