Oxidative stress activates a positive feedback between the γ- and β-secretase cleavages of the β-amyloid precursor protein

被引：285

作者：

Tamagno, Elena ^{[1
]}

Guglielmotto, Michela ^{[1
]}

Aragno, Manuela ^{[1
]}

Borghi, Roberta ^{[2
]}

Autelli, Riccardo ^{[1
]}

Giliberto, Luca ^{[2
]}

Muraca, Giuseppe ^{[3
]}

Danni, Oliviero ^{[1
]}

Zhu, Xiongwei ^{[4
]}

Smith, Mark A. ^{[4
]}

Perry, George ^{[4
]}

Jo, Dong-Gyu ^{[5
,6
]}

Mattson, Mark P. ^{[5
]}

Tabaton, Massimo ^{[2
]}

机构：

[1] Univ Turin, Dept Expt Med & Oncol, Turin, Italy

[2] Univ Genoa, Dept Neurosci, Genoa, Italy

[3] Univ Turin, Dept Anat Pharmacol & Forens Med, Turin, Italy

[4] Case Western Reserve Univ, Cleveland, OH 44106 USA

[5] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA

[6] Sungkyunkwan Univ, Coll Pharm, Suwon, South Korea

来源：

JOURNAL OF NEUROCHEMISTRY | 2008年 / 104卷 / 03期

关键词：

Alzheimer's disease; BACE1; JNK pathway oxidative stress; gamma-secretase;

D O I：

10.1111/j.1471-4159.2007.05072.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Sequential cleavages of the beta-amyloid precursor protein cleaving enzyme 1 (BACE1) by beta-secretase and gamma-secretase generate the amyloid beta-peptides, believed to be responsible of synaptic dysfunction and neuronal cell death in Alzheimer's disease (AD). Levels of BACE1 are increased in vulnerable regions of the AD brain, but the underlying mechanism is unknown. Here we show that oxidative stress (OS) stimulates BACE1 expression by a mechanism requiring gamma-secretase activity involving the c-jun N-terminal kinase (JNK)/c-jun pathway. BACE1 levels are increased in response to OS in normal cells, but not in cells lacking presenilins or amyloid precursor protein. Moreover, BACE1 is induced in association with OS in the brains of mice subjected to cerebral ischaemia/reperfusion. The OS-induced BACE1 expression correlates with an activation of JNK and c-jun, but is absent in cultured cells or mice lacking JNK. Our findings suggest a mechanism by which OS induces BACE1 transcription, thereby promoting production of pathological levels of amyloid beta in AD.

引用

页码：683 / 695

页数：13

共 64 条

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