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.
Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089-0191, USA.,
Apoptosis Regulatory Proteins
Bcl-2-Like Protein 11
Gene Expression Regulation
JNK Mitogen-Activated Protein Kinases
Proto-Oncogene Proteins c-bcl-2
RNA, Small Interfering
Pub Type(s)Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.