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Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide-induced neuronal death.

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.

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  • Authors+Show Affiliations

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

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    Source

    MeSH

    Amyloid beta-Peptides
    Animals
    Anthracenes
    Apoptosis
    Apoptosis Regulatory Proteins
    Bcl-2-Like Protein 11
    Carrier Proteins
    Cerebral Cortex
    Cytochromes c
    Enzyme Activation
    Estradiol
    Estrogen Receptor Modulators
    Fulvestrant
    Gene Expression Regulation
    JNK Mitogen-Activated Protein Kinases
    Membrane Proteins
    Mitochondria
    Mitochondrial Proteins
    Nerve Tissue Proteins
    Neurons
    Neuroprotective Agents
    Peptide Fragments
    Protein Kinase Inhibitors
    Proteins
    Proto-Oncogene Proteins
    Proto-Oncogene Proteins c-bcl-2
    RNA, Messenger
    RNA, Small Interfering
    Rats
    Rats, Sprague-Dawley
    Receptors, Estrogen
    Reverse Transcriptase Polymerase Chain Reaction
    Transfection

    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 -