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

Elena Tamagno, Michela Guglielmotto, Manuela Aragno, Roberta Borghi, Riccardo Autelli, Luca Giliberto, Giuseppe Muraca, Oliviero Danni, Xiongwei Zhu, Mark A. Smith, George Perry, Dong Gyu Jo, Mark P. Mattson, Massimo Tabaton

Research output: Contribution to journalArticlepeer-review

271 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)683-695
Number of pages13
JournalJournal of Neurochemistry
Volume104
Issue number3
DOIs
StatePublished - Feb 2008
Externally publishedYes

Keywords

  • Alzheimer's Disease
  • BACE1; JNK pathway; oxidative stress; γ-secretase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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