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J. Biol. Chem., Vol. 283, Issue 25, 17721-17730, June 20, 2008

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Hydrogen Peroxide Promotes Aβ Production through JNK-dependent Activation of -Secretase^*

Chengyong Shen, Yongfeng Chen, Huaqing Liu, Kejing Zhang, Ting Zhang, Anning Lin, and Naihe Jing¹

From the Laboratory of Molecular Cell Biology, Key Laboratory of Stem Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China and the Ben May Department for Cancer Research, the University of Chicago, Chicago, Illinois 60637

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 -secretase. Although oxidative stress has been implicated in the AD pathogenesis 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 -secretase. Treatment with H₂O₂ induced significant increase in the levels of intracellular and secreted Aβ in human neuroblastoma SH-SY5Y cells. Although -secretase-mediated cleavage of APP or C99 was enhanced upon H₂O₂ treatment, expression of APP or its /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 -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 -secretase-mediated APP cleavage and Aβ production.

Received for publication, January 2, 2008 , and in revised form, April 23, 2008.

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^* This work was supported, in whole or in part, by National Institutes of Health Grant CA100460 (to A. L.). This work was also supported by National Natural Science Foundation of China Grants 30623003 and 30721065 (to N. J.), National Key Basic Research and Development Program of China Grants 2005CB522704, 2006CB943902, and 2007CB947101 (to N. J.), National 863 Plan Project 2006AA02Z186 (to N. J.), Shanghai Key Project of Basic Science Research Grants 06DJ14001 and 06DZ22032 (to N. J.), and Council of Shanghai Municipal Government for Science and Technology Grant 05814578 (to N. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

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¹ To whom correspondence should be addressed. Tel.: 86-21-5492-1381; Fax: 86-21-5492-1011; E-mail: njing{at}sibs.ac.cn.

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