Hydrogen peroxide promotes A beta production through JNK-dependent activation of gamma-secretase

	Hydrogen peroxide promotes A beta production through JNK-dependent activation of gamma-secretase
	Shen, CY; Chen, YF; Liu, HQ; Zhang, KJ; Zhang, T; Lin, A; Jing, NH
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2008
卷号	283 期号:25 页码:17721-17730
通讯作者	Jing, NH (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Key Lab Stem Cell Biol,Lab Mol Cell Biol, Shanghai 200031, Peoples R China.,njing@sibs.ac.cn
英文摘要	Accumulation of senile plaques composed of amyloid beta-peptide (A beta) is a pathological hallmark of Alzheimer disease ( AD), and A beta is generated through the sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase. Although oxidative stress has been implicated in the AD pathogenesis by inducing A beta production, the underlying mechanism remains elusive. Here we show that the pro-oxidant H(2)O(2) promotes A beta production through c-Jun N-terminal kinase (JNK)-dependent activation of gamma-secretase. Treatment with H(2)O(2) induced significant increase in the levels of intracellular and secreted A beta in human neuroblastoma SH-SY5Y cells. Although gamma-secretase-mediated cleavage of APP or C99 was enhanced upon H(2)O(2) treatment, expression of APP or its alpha/beta-secretase-mediated cleavage was not affected. Silencing of the stress-activated JNK by small interfering RNA or the specific JNK inhibitor SP600125 reduced H(2)O(2)-induced gamma-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 gamma-secretase-mediated APP cleavage and A beta production.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	AMYLOID PRECURSOR PROTEIN ; NECROSIS-FACTOR-ALPHA ; ALZHEIMERS-DISEASE ; OXIDATIVE STRESS ; NEUROBLASTOMA-CELLS ; H2O2 ACCUMULATION ; TRANSGENIC MICE ; KINASE ; PRESENILIN ; CLEAVAGE
收录类别	SCI
语种	英语
WOS记录号	WOS:000256720600078
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/1473]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Shen, CY,Chen, YF,Liu, HQ,et al. Hydrogen peroxide promotes A beta production through JNK-dependent activation of gamma-secretase[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2008,283(25):17721-17730.
APA	Shen, CY.,Chen, YF.,Liu, HQ.,Zhang, KJ.,Zhang, T.,...&Jing, NH.(2008).Hydrogen peroxide promotes A beta production through JNK-dependent activation of gamma-secretase.JOURNAL OF BIOLOGICAL CHEMISTRY,283(25),17721-17730.
MLA	Shen, CY,et al."Hydrogen peroxide promotes A beta production through JNK-dependent activation of gamma-secretase".JOURNAL OF BIOLOGICAL CHEMISTRY 283.25(2008):17721-17730.