Glycogen synthase kinase 3beta links neuroprotection by 17beta-estradiol to key Alzheimer processes.
Estrogen exerts many of its receptor-mediated neuroprotective functions through the activation of various intracellular signal transduction pathways including the mitogen activating protein kinase (MAPK), phospho inositol-3 kinase and protein kinase C pathways. Here we have used a hippocampal slice culture model of kainic acid-induced neurotoxic cell death to show that estrogen can protect against oxidative cell death. We have previously shown that MAPK and glycogen synthase kinase-3beta (GSK-3beta) are involved in the cell death/cell survival induced by kainic acid. In this model and other cellular and in vivo models we have shown that estrogen can also cause the phosphorylation and hence inactivation of GSK-3beta, a known mediator of neuronal cell death. The effect of estrogen on GSK-3beta activity is estrogen receptor mediated. Further, this estrogen/GSK-3beta interaction may have functional consequences in cellular models of some key pathogenic pathways associated with Alzheimer's disease. More specifically, estrogen affects the basal levels of tau phosphorylation at a site known to be phosphorylated by GSK-3beta. Taken together, these data indicate a novel molecular and functional link between estrogen and GSK-3beta and may have implications for estrogen receptor modulation as a target for the prevention of neurodegenerative disorders.
Goodenough
S
S
Institute for Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University, Medical School, Duesbergweg 6, D-55099 Mainz, Germany.
Schleusner
D
D
Pietrzik
C
C
Skutella
T
T
Behl
C
C
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004958:Estradiol / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011247:Pregnancy; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D014443:Tyrosine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018690:Excitatory Amino Acid Agonists; C085349:PHF-1 monoclonal antibody; D013778:Tetrazolium Salts; D013844:Thiazoles; D016875:tau Proteins; D011419:Propidium; D014443:Tyrosine; D012694:Serine; D004958:Estradiol; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C022616:thiazolyl blue; D007608:Kainic Acid