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The Journal of Neuroscience, February 7, 2007, 27(6):1422-1433; doi:10.1523/JNEUROSCI.2382-06.2007

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Cellular/Molecular
Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against ß-Amyloid Peptide-Induced Neuronal Death

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

Davis School of Gerontology, University of Southern California, Los Angeles, California 90089

Correspondence should be addressed to Dr. Christian J. Pike, Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191. Email: cjpike{at}usc.edu

Estrogen is neuroprotective against a variety of insults, including ß-amyloid peptide (Aß); however, the underlying mechanism(s) is not fully understood. Here, we report that 17ß-estradiol (E2) selectively regulates neuronal expression of the Bcl-2 family (bcl-2, bcl-x, bcl-w, bax, bak, bad, bik, bnip3, bid, and bim). In primary cerebrocortical neuron cultures under basal conditions, we observe that E2 upregulates expression of antiapoptotic Bcl-w and downregulates expression of proapoptotic Bim in an estrogen receptor (ER)-dependent manner. In the presence of toxic levels of Aß, we observe that E2 attenuates indices of neuronal apoptosis: c-Jun N-terminal kinase (JNK)-dependent downregulation of Bcl-w and upregulation of Bim, mitochondrial release of cytochrome c and Smac, and cell death. These neuroprotective effects of E2 against Aß-induced apoptosis are mimicked by the JNK inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one). In addition, E2 attenuates Aß-induced JNK phosphorylation in an ER-dependent manner, but does not affect basal levels of JNK phosphorylation. These results suggest that E2 may reduce Aß-induced neuronal apoptosis at least in part by two complementary pathways: (1) ER-dependent, JNK-independent upregulation of Bcl-w and downregulation of Bim under basal conditions, and (2) ER-dependent inhibition of Aß-induced JNK activation and subsequent JNK-dependent downregulation of Bcl-w and upregulation of Bim, resulting in mitochondrial release of cytochrome c and Smac and eventual cell death. These data provide new understanding into the mechanisms contributing to estrogen neuroprotection, a neural function with potential therapeutic relevance to Alzheimer's disease.

Key words: ß-amyloid; apoptosis; Bcl-w; Bim; c-Jun N-terminal kinase; estrogen

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Received June 5, 2006; revised Dec. 6, 2006; accepted Dec. 8, 2006.

Correspondence should be addressed to Dr. Christian J. Pike, Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191. Email: cjpike{at}usc.edu

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