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The Journal of Neuroscience, February 2, 2005, 25(5):1149-1158; doi:10.1523/JNEUROSCI.4736-04.2005

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Neurobiology of Disease
-Amyloid-Induced Neuronal Apoptosis Involves c-Jun N-Terminal Kinase-Dependent Downregulation of Bcl-w

Mingzhong Yao, Thuy-Vi V. Nguyen, and Christian J. Pike

Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089

-Amyloid protein (A) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). A directly induces neuronal apoptosis, suggesting an important role of A neurotoxicity in AD neurodegeneration. However, the mechanism(s) of A-induced neuronal apoptosis remain incompletely defined. In this study, we report that A-induced neuronal death is preceded by selective alterations in expression of the Bcl-2 family of apoptosis-related genes. Specifically, we observe that A 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.A-induced downregulation of Bcl-w appears to contribute to the mechanism of apoptosis, because A-induced neuronal death was significantly increased by Bcl-w suppression but significantly reduced by Bcl-w overexpression. Downstream of Bcl-w, A-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 A-induced Bcl-w downregulation and Smac release. We observed that A rapidly activates c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK effectively inhibited all measures of A apoptosis: Bcl-w downregulation, Smac release, and neuronal death. Together, these results suggest that the mechanism of A-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 A-induced apoptosis promises to accelerate development of neuroprotective interventions for the treatment of AD.

Key words: -amyloid; Bcl-w; Smac; c-Jun N-terminal kinase; apoptosis; Alzheimer's disease

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Received June 1, 2004; revised November 18, 2004; accepted December 11, 2004.

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