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Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide-induced neuronal death.
J Neurosci 2007; 27(6):1422-33JN

Abstract

Estrogen is neuroprotective against a variety of insults, including beta-amyloid peptide (Abeta); however, the underlying mechanism(s) is not fully understood. Here, we report that 17beta-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 Abeta, 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 Abeta-induced apoptosis are mimicked by the JNK inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one). In addition, E2 attenuates Abeta-induced JNK phosphorylation in an ER-dependent manner, but does not affect basal levels of JNK phosphorylation. These results suggest that E2 may reduce Abeta-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 Abeta-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.

Authors+Show Affiliations

Davis School of Gerontology, University of Southern California, Los Angeles, California 90089, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17287517

Citation

Yao, Mingzhong, et al. "Estrogen Regulates Bcl-w and Bim Expression: Role in Protection Against Beta-amyloid Peptide-induced Neuronal Death." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 27, no. 6, 2007, pp. 1422-33.
Yao M, Nguyen TV, Pike CJ. Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide-induced neuronal death. J Neurosci. 2007;27(6):1422-33.
Yao, M., Nguyen, T. V., & Pike, C. J. (2007). Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide-induced neuronal death. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 27(6), pp. 1422-33.
Yao M, Nguyen TV, Pike CJ. Estrogen Regulates Bcl-w and Bim Expression: Role in Protection Against Beta-amyloid Peptide-induced Neuronal Death. J Neurosci. 2007 Feb 7;27(6):1422-33. PubMed PMID: 17287517.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide-induced neuronal death. AU - Yao,Mingzhong, AU - Nguyen,Thuy-Vi V, AU - Pike,Christian J, PY - 2007/2/9/pubmed PY - 2007/3/7/medline PY - 2007/2/9/entrez SP - 1422 EP - 33 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 27 IS - 6 N2 - Estrogen is neuroprotective against a variety of insults, including beta-amyloid peptide (Abeta); however, the underlying mechanism(s) is not fully understood. Here, we report that 17beta-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 Abeta, 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 Abeta-induced apoptosis are mimicked by the JNK inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one). In addition, E2 attenuates Abeta-induced JNK phosphorylation in an ER-dependent manner, but does not affect basal levels of JNK phosphorylation. These results suggest that E2 may reduce Abeta-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 Abeta-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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/17287517/Estrogen_regulates_Bcl_w_and_Bim_expression:_role_in_protection_against_beta_amyloid_peptide_induced_neuronal_death_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=17287517 DB - PRIME DP - Unbound Medicine ER -