Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3 beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: implications for Alzheimer's disease.
We have shown previously that glycogen synthase kinase-3 beta (GSK-3 beta), cyclin-dependent kinase 5, and c-Jun NH(2)-terminal kinase become overactivated and hyperphosphorylate tau in heat-shocked female rats. This hyperphosphorylation of tau 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 microg of 17 beta-estradiol benzoate (EB), or 250 microg 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 beta at 0-6 h after heat shock toward human recombinant tau, bovine tau, 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 (pSer(9)) and activity-enhanced (pTyr(216)) GSK-3 beta showed marked increase of pSer(9)- and decrease of pTyr(216)-GSK-3 beta 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 NH(2)-terminal kinase was gonadal hormone-independent. The serum concentrations of testosterone and 17 beta-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 tau by inhibiting the heat shock-induced overactivation of GSK-3 beta and suggest that androgens given to aging men or, in combination with estrogens, to postmenopausal women could prevent or delay Alzheimer's disease.
Papasozomenos
Sozos Ch
SCh
Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, Houston, TX 77030, USA. Sozos.C.Papasozomenos@uth.tmc.edu
Shanavas
Alikunju
A
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005260:Female; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006358:Hot Temperature; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010052:Ovariectomy; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D013739:Testosterone; D004958:Estradiol; D038341:Glycogen Synthase Kinases; D051360:Cyclin-Dependent Kinase 5; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C495905:CDK5 protein, human; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3