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.

Abstract

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.

• Authors: Sozos Ch Papasozomenos, Alikunju Shanavas
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 99 Issue 3 Pg. 1140-5 (Feb 05 2002) ISSN: 0027-8424 [Print] United States
• PMID: 11805297 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• tau Proteins
• Testosterone
• Estradiol
• Glycogen Synthase Kinases
• Cyclin-Dependent Kinase 5
• Calcium-Calmodulin-Dependent Protein Kinases
• CDK5 protein, human
• Cdk5 protein, rat
• Cyclin-Dependent Kinases
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• Glycogen Synthase Kinase 3

Topics

• Alzheimer Disease (metabolism)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinases (drug effects, metabolism)
• Cattle
• Cyclin-Dependent Kinase 5
• Cyclin-Dependent Kinases (drug effects, metabolism)
• Enzyme Activation
• Estradiol (pharmacology)
• Estrogen Replacement Therapy
• Female
• Glycogen Synthase Kinase 3
• Glycogen Synthase Kinases
• Hot Temperature
• Humans
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases (metabolism)
• Ovariectomy
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Testosterone (pharmacology)
• tau Proteins (metabolism)