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Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease

By Sozos Ch. Papasozomenos and Alikunju Shanavas

Abstract

We have shown previously that glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5, and c-Jun NH2-terminal kinase become overactivated and hyperphosphorylate τ in heat-shocked female rats. This hyperphosphorylation of τ is estrogen-independent, prevented by androgens, and similar to Alzheimer's disease. In this study, ovariectomized (OVX) Sprague-Dawley rats (n = 75) received daily injections of 10 μg of 17β-estradiol benzoate (EB), or 250 μg of testosterone propionate (TP), or both EB and TP, or sesame oil (SO) vehicle for 4–6 weeks. In kinase assays of forebrain homogenates, overactivation of GSK-3β at 0–6 h after heat shock toward human recombinant τ, bovine τ, and phosphoglycogen synthase peptide 2 was prevented in OVX + TP and OVX + (EB + TP) but not in sham-OVX + SO, OVX + SO, and OVX + EB. Abs against inactive (pSer9) and activity-enhanced (pTyr216) GSK-3β showed marked increase of pSer9- and decrease of pTyr216-GSK-3β in both OVX + TP and OVX + (EB + TP) but not in sham-OVX + SO, OVX + SO, and OVX + EB. EB enhanced the overactivation of cyclin-dependent kinase 5. The activity of c-Jun NH2-terminal kinase was gonadal hormone-independent. The serum concentrations of testosterone and 17β-estradiol were 2.53 ng/ml and 201 pg/ml in OVX + TP and OVX + EB, respectively. These findings demonstrate that testosterone prevents the hyperphosphorylation of τ by inhibiting the heat shock-induced overactivation of GSK-3β and suggest that androgens given to aging men or, in combination with estrogens, to postmenopausal women could prevent or delay Alzheimer's disease

Topics: Biological Sciences
Publisher: The National Academy of Sciences
Year: 2002
DOI identifier: 10.1073/pnas.032646799
OAI identifier: oai:pubmedcentral.nih.gov:122157
Provided by: PubMed Central
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