Okadaic acid induces tau phosphorylation in SH-SY5Y cells in an estrogen-preventable manner.
One of the pathological hallmarks of Alzheimer's disease (AD) is neurofibrillary tangles (NFTs), which are composed of abnormally hyperphosphorylated tau, but the mechanism of tau hyperphosphorylation in AD is still unclear. To investigate the effects of estrogens on tau phosphorylation, SH-SY5Y cells were treated with okadaic acid (OA), a serine/threonine phosphatase inhibitor, to induce tau phosphorylation and the effects of estrogen were observed by co-treatment with 17beta-estradiol (E2). We found that OA induced in vitro tau hyperphosphorylation, which was prevented by E2 in a dose-dependent manner. This effect of E2 was partially blocked by an estrogen receptor (ER) antagonist, ICI 182,780. In addition to tau hyperphosphorylation, inhibition of serine/threonine phosphorylation induced upregulation of cdk5 levels, which was attenuated by E2 in a manner that was counteracted by ICI 182,780. Our results show that cdk5 is involved in OA-induced tau hyperphosphorylation, and estrogens ameliorate the tau hyperphosphorylation, which may be mediated in part by ER.
Zhang
Zhang
Z
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Simpkins
James W
JW
D015153:Blotting, Western; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019319:Okadaic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D011960:Receptors, Estrogen; C118136:TPPP protein, human; D016875:tau Proteins; D019319:Okadaic Acid; D000077267:Fulvestrant; D004958:Estradiol; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D010749:Phosphoprotein Phosphatases
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