Hydrogen peroxide promotes Aβ production through JNK-dependent activation of γ-secretase

Chengyong Shen, Yongfeng Chen, Huaqing Liu, Kejing Zhang, Ting Zhang, Anning Lin, Naihe Jing

Research output: Contribution to journalArticle

132 Scopus citations

Abstract

Accumulation of senile plaques composed of amyloid β-peptide (Aβ) is a pathological hallmark of Alzheimer disease (AD), and Aβ is generated through the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretase. Although oxidative stress has been implicated in theADpathogenesis by inducing Aβ production, the underlying mechanism remains elusive. Here we show that the pro-oxidant H2O2 promotes Aβ production through c-Jun N-terminal kinase (JNK)-dependent activation of γ-secretase. Treatment with H2O2 induced significant increase in the levels of intracellular and secreted Aβ in human neuroblastoma SH-SY5Y cells. Although γ-secretase-mediated cleavage of APP or C99 was enhanced upon H2O2 treatment, expression of APP or its α/β-secretase-mediated cleavage was not affected. Silencing of the stress-activated JNK by small interfering RNA or the specific JNK inhibitor SP600125 reduced H2O2-induced γ-secretase-mediated cleavage of APP. JNK activity was augmented in human brain tissues from AD patients and active JNK located surrounding the senile plaques in the brain of AD model mouse. Our data suggest that oxidative stress-activated JNK may contribute to senile plaque expansion through the promotion of γ-secretase-mediated APP cleavage and Aβ production.

Original languageEnglish (US)
Pages (from-to)17721-17730
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number25
DOIs
StatePublished - Jun 20 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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