Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w.
beta-Amyloid protein (Abeta) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Abeta directly induces neuronal apoptosis, suggesting an important role of Abeta neurotoxicity in AD neurodegeneration. However, the mechanism(s) of Abeta-induced neuronal apoptosis remain incompletely defined. In this study, we report that Abeta-induced neuronal death is preceded by selective alterations in expression of the Bcl-2 family of apoptosis-related genes. Specifically, we observe that Abeta significantly reduces expression of antiapoptotic Bcl-w and Bcl-x(L), mildly affects expression of bim, Bcl-2, and bax, but does not alter expression of bak, bad, bik, bid, or BNIP3.Abeta-induced downregulation of Bcl-w appears to contribute to the mechanism of apoptosis, because Abeta-induced neuronal death was significantly increased by Bcl-w suppression but significantly reduced by Bcl-w overexpression. Downstream of Bcl-w, Abeta-induced neuronal apoptosis is characterized by mitochondrial release of second mitochondrion-derived activator of caspase (Smac), an important precursor event to cell death. We observed that Smac release was potentiated by suppression of Bcl-w and reduced by overexpression of Bcl-w. Next, we investigated the upstream mediator of Abeta-induced Bcl-w downregulation and Smac release. We observed that Abeta rapidly activates c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK effectively inhibited all measures of Abeta apoptosis: Bcl-w downregulation, Smac release, and neuronal death. Together, these results suggest that the mechanism of Abeta-induced neuronal apoptosis sequentially involves JNK activation, Bcl-w downregulation, and release of mitochondrial Smac, followed by cell death. Complete elucidation of the mechanism of Abeta-induced apoptosis promises to accelerate development of neuroprotective interventions for the treatment of AD.
Yao
Mingzhong
M
Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089-0191, USA.
Nguyen
Thuy-Vi V
TV
Pike
Christian J
CJ
D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D024101:Mitochondrial Proteins / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051020:bcl-X Protein
D016229:Amyloid beta-Peptides; D000873:Anthracenes; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C494813:Bcl2l1 protein, rat; C000606778:Bcl2l11 protein, rat; C491072:Bcl2l2 protein, rat; D002352:Carrier Proteins; C489013:DIABLO protein, rat; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C074636:amyloid beta-protein (25-35); D051020:bcl-X Protein; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases