Evidence of oxidative stress-induced BNIP3 expression in amyloid beta neurotoxicity

The formation of A beta and its subsequent deposition in senile plaques are considered to be initial events that lead to a cascade of pathological changes in AD. Mediators of A beta-induced oxidative stress are known to cause oxidative damage to macromolecules. However, the molecular mechanisms by which A beta-induced oxidative stress leads to neuronal cell death are not fully understood. Here we show that A beta-induced oxidative stress activates the prodeath gene BNIP3. A beta treatment results in mitochondrial dysfunction, accumulation of reactive oxygen species, and subsequent expression of BNIP3 in rat primary cortical neurons. Pretreatment with antioxidants abolished A beta-induced BNIP3 expression and attenuated cell death, demonstrating the role of oxidative stress in BNIP3 induction. A beta-induced BNIP3 expression may be mediated by hypoxia-inducible factor-1 (HIF-1) because A beta-treatment induced accumulation and nuclear translocation of HIF-1 and knock-down of HIF-1 by RNAi inhibited BNIP3 expression. Finally, knockdown of BNIP3 reduced A beta-induced neuronal death. Together, these results suggest a potential pathological role of BNIP3 in the etiology of AD. (c) 2007 Elsevier B.V. All rights reserved.