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

We have shown previously that glycogen synthase kinase-3 (GSK-3 ), cyclin-dependent kinase 5, and c-Jun NH2-terminal kinase become overactivated and hyperphosphorylate in heat-shocked female rats. This hyperphosphorylation of 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 g of 17 -estradiol benzoate (EB), or 250 g 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-3 at 0–6 h after heat shock toward human recombinant , bovine , 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-3 showed marked increase of pSer9and decrease of pTyr216-GSK-3 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 17 -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 by inhibiting the heat shock-induced overactivation of GSK-3 and suggest that androgens given to aging men or, in combination with estrogens, to postmenopausal women could prevent or delay Alzheimer’s disease.