The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1α
Article first published online: 16 DEC 2008
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 108, Issue 4, pages 1045–1056, February 2009
How to Cite
Guglielmotto, M., Aragno, M., Autelli, R., Giliberto, L., Novo, E., Colombatto, S., Danni, O., Parola, M., Smith, M. A., Perry, G., Tamagno, E. and Tabaton, M. (2009), The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1α. Journal of Neurochemistry, 108: 1045–1056. doi: 10.1111/j.1471-4159.2008.05858.x
- Issue published online: 19 JAN 2009
- Article first published online: 16 DEC 2008
- Received October 13, 2008; revised manuscript received December 3, 2008; accepted December 6, 2008.
- Alzheimer’ disease;
- β-site APP cleaving enzyme;
- hypoxia inducible factor 1α;
- neuroblastoma cells;
- oxidative stress
While it is well established that stroke and cerebral hypoperfusion are both significant risk factors for Alzheimer’s disease, the molecular link between ischemia and amyloid precursor protein processing has only been recently established. Specifically, hypoxia significantly increases β-site APP cleaving enzyme (BACE1) gene transcription through the over-expression of hypoxia inducible factor 1α, resulting in increased BACE1 secretase activity and amyloid-β production. In this study, we significantly extend these findings both in vitro, in differentiated SK-N-BE neuroblastoma cells, and in vivo, in rats subjected to cerebral ischemia, showing that hypoxia up-regulates BACE1 expression through a biphasic mechanism. The early post-hypoxic up-regulation of BACE1 depends on the production of reactive oxygen species mediated by the sudden interruption of the mitochondrial electron transport chain, while the later expression of BACE1 is caused by hypoxia inducible factor 1α activation. The involvement of reactive oxygen species released by mitochondria in the BACE1 up-regulation was confirmed by the complete protection exerted by complex I inhibitors such as rotenone and diphenyl-phenylen iodonium. Moreover, the oxidative stress-mediated up-regulation of BACE1 is mediated by c-jun N terminal kinase pathway as demonstrated by the protection exerted by the silencing of c-jun N-terminal kinase isoforms 1 and 2. Our study strengthens the hypothesis that oxidative stress is a basic common mechanism of amyloid-β accumulation.