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

NEUROBIOLOGY OF AGING

卷:31

Article

Jo, Dong-Gyu^1,2  Arumugam, Thiruma V.¹  Woo, Ha-Na²  Park, Jong-Sung²  Tang, Sung-Chun^1,3  Mughal, Mohamed¹  Hyun, Dong-Hoon^1,4  Park, Jun-Hyung²  Choi, Yun-Hyung²  Gwon, A-Ryeong²  Camandola, Simonetta¹  Cheng, Aiwu¹  Cai, Huaibin^5,6  Song, Weihong⁷  Markesbery, William R.⁸  Mattson, Mark P.^1,9 

[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

关键词: beta-Secretase;    Alzheimer's disease;    Oxidative stress;    gamma-Secretase;   

DOI  :  10.1016/j.neurobiolaging.2008.07.003

来源: Elsevier

【 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.

【 授权许可】

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