More women than men have Alzheimer's disease (AD), suggesting that loss of estrogen may increase the risk for AD in postmenopausal women. Recent studies to demonstrate that estrogen protects Alzheimer's patients have had mixed results. In the January 22 advanced online publication in PNAS, Sozos Papasozomenos and Alikunju Shanavas at the University of Texas demonstrate that testosterone may prove beneficial in preventing the disease.
The researchers used an animal model to test the effects of testosterone and estradiol on heat shock induced phosphorylation of tau, the major component of the neurofibrillary tangles that are associated with AD. They found that testosterone, but not estradiol, could prevent phosphorylation of the microtubule-associated protein, specifically at Ser404.
Extracts from the forebrains of heat-shocked rats were tested for activity of glycogen synthase kinase-3β GSK-3β , cyclin-dependent kinase 5 (Cdk5), and c-Jun N-terminal kinase (JNK), which had previously been shown to be involved in tau phosphorylation. In the presence of testosterone, only GSK-3β activity was affected, being significantly reduced. Using phosphospecific antibodies, the authors showed the androgen to prevent phosphorylation of Tyr216, which is required for full activation of the kinase.
This work provides a molecular basis for previous observations that men with lower plasma testosterone are more susceptible to developing Alzheimer's.—Tom Fagan
- Raber J, Bongers G, LeFevour A, Buttini M, Mucke L. Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci. 2002 Jun 15;22(12):5204-9. PubMed.
- Papasozomenos SC, Shanavas A. 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. Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1140-5. PubMed.