Estrogen-mediated neuroprotection against beta-amyloid toxicity requires expression of estrogen receptor alpha or beta and activation of the MAPK pathway.
It is well documented that estrogen can activate rapid signaling pathways in a variety of cell types. These non-classical effects of estrogen have been reported to be important for cell survival after exposure to a variety of neurotoxic insults. Since direct evidence of the ability of the estrogen receptors (ERs) alpha and/or beta to mediate such responses is lacking, the hippocampal-derived cell line HT22 was stably transfected with either ERalpha (HTERalpha) or ERbeta (HTERbeta). In HTERalpha and HTERbeta cells, but not untransfected cells, an increase in ERK2 phosphorylation was measured within 15 min of 17beta-estradiol treatment. The ER antagonist ICI 182, 780 (1 microm) and the MEK inhibitor, PD98059 (50 microm) blocked this increase in ERK2 phosphorylation. Treatment of HT22, HTERalpha and HTERbeta cells with the beta-amyloid peptide (25-35) (10 micro m) resulted in a significant decrease in cell viability. Pre-treatment for 15 min with 10 nm 17beta-estradiol resulted in a 50% increase in the number of living cells in HTERalpha and HTERbeta cells, but not in HT22 cells. Finally, ICI 182, 780 and PD98059 prevented 17beta-estradiol-mediated protection. This study demonstrates that both ERalpha and ERbeta can couple to rapid signaling events that mediate estrogen-elicited neuroprotection.
Fitzpatrick
Jennifer L
JL
Department of Pharmacology, University of Washington, Seattle, USA. fretlanj@ohsu.edu
Mize
Amy L
AL
Wade
Christian B
CB
Harris
Julie A
JA
Shapiro
Robert A
RA
Dorsa
Daniel M
DM
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D010446:Peptide Fragments; D011960:Receptors, Estrogen; C074636:amyloid beta-protein (25-35); D004958:Estradiol; D019950:Mitogen-Activated Protein Kinase 1