Evidence of oxidative stress-induced BNIP3 expression in amyloid beta neurotoxicity.
The formation of Abeta 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 Abeta-induced oxidative stress are known to cause oxidative damage to macromolecules. However, the molecular mechanisms by which Abeta-induced oxidative stress leads to neuronal cell death are not fully understood. Here we show that Abeta-induced oxidative stress activates the pro-death gene BNIP3. Abeta treatment results in mitochondrial dysfunction, accumulation of reactive oxygen species, and subsequent expression of BNIP3 in rat primary cortical neurons. Pretreatment with antioxidants abolished Abeta-induced BNIP3 expression and attenuated cell death, demonstrating the role of oxidative stress in BNIP3 induction. Abeta-induced BNIP3 expression may be mediated by hypoxia-inducible factor-1 (HIF-1) because Abeta-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 Abeta-induced neuronal death. Together, these results suggest a potential pathological role of BNIP3 in the etiology of AD.
Zhang
Surong
S
Department of Human Anatomy and Cell Science, University of Manitoba Faculty of Medicine, 730 William Avenue, Winnipeg, Manitoba, Canada R3E 0W3.
Zhang
Zhengfeng
Z
Sandhu
Garry
G
Ma
Xiuli
X
Yang
Xuefen
X
Geiger
Jonathan D
JD
Kong
Jiming
J
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D009474:Neurons / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; C505650:BNIP3 protein, rat; D051793:Hypoxia-Inducible Factor 1; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009498:Neurotoxins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; C074636:amyloid beta-protein (25-35)