Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer's disease.
Recent findings indicate that estrogen is neuroprotective, a cellular effect that may contribute to its clinical benefits in delaying the development of Alzheimer's disease. In this report, we identify a novel neuronal action of estrogen that may contribute to its neuroprotective mechanism(s). Specifically, we report that estrogen significantly increases the expression of the antiapoptotic protein Bcl-xL in cultured hippocampal neurons. This effect presumably reflects classic estrogen transcriptional regulation, as we identified a putative estrogen response element in the bcl-x gene. Estrogen-induced enhancement of Bcl-xL is associated with a reduction in measures of beta-amyloid-induced apoptosis, including inhibition of both caspase-mediated proteolysis and neurotoxicity. A similar relationship between estrogen, Bcl-xL expression, and resistance to degeneration was also observed in human hippocampus. We report neuronal colocalization of estrogen receptor and Bcl-xL immunoreactivities that is most prominent in hippocampal subfield CA3, a region that shows relatively little immunoreactivity to paired helical filament-1, a marker of Alzheimer's disease neurodegeneration. These data suggest a novel mechanism of estrogen neuroprotection that may be relevant to estrogen's suggested ability to modulate neuronal viability across the life span, from neural sexual differentiation and development through age-related neurodegenerative conditions.
Pike
C J
CJ
Institute for Brain Aging and Dementia, Gillespie Neuroscience Research Facility, University of California-Irvine, 92697-4540, USA.
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000906:Antibodies; D017209:Apoptosis / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000032:analysis / Q000276:immunology; D051020:bcl-X Protein
D016229:Amyloid beta-Peptides; D000906:Antibodies; C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D051020:bcl-X Protein; D004958:Estradiol; D020169:Caspases