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Oxidative stress activates a positive feedback between the γ‐ and β‐secretase cleavages of the β‐amyloid precursor protein
Author(s) -
Tamagno Elena,
Guglielmotto Michela,
Aragno Manuela,
Borghi Roberta,
Autelli Riccardo,
Giliberto Luca,
Muraca Giuseppe,
Danni Oliviero,
Zhu Xiongwei,
Smith Mark A.,
Perry George,
Jo DongGyu,
Mattson Mark P.,
Tabaton Massimo
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05072.x
Subject(s) - presenilin , amyloid precursor protein , bace1 as , amyloid precursor protein secretase , oxidative stress , p3 peptide , c jun , microbiology and biotechnology , kinase , β amyloid , chemistry , amyloid (mycology) , alzheimer's disease , transcription factor , neuroscience , biochemistry , biology , medicine , gene , disease , inorganic chemistry
Sequential cleavages of the β‐amyloid precursor protein cleaving enzyme 1 (BACE1) by β‐secretase and γ‐secretase generate the amyloid β‐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 γ‐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 β in AD.