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

Dong Gyu Jo, Thiruma V. Arumugam, Ha Na Woo, Jong Sung Park, Sung Chun Tang, Mohamed Mughal, Dong Hoon Hyun, Jun Hyung Park, Yun Hyung Choi, A. Ryeong Gwon, Simonetta Camandola, Aiwu Cheng, Huaibin Cai, Weihong Song, William R. Markesbery, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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.

Original languageEnglish
Pages (from-to)917-925
Number of pages9
JournalNeurobiology of Aging
Volume31
Issue number6
DOIs
StatePublished - Jun 2010

Keywords

  • β-Secretase
  • γ-Secretase
  • Alzheimer's disease
  • Oxidative stress

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