The heat shock-induced hyperphosphorylation of tau is estrogen-independent and prevented by androgens: implications for Alzheimer disease.

Abstract

We have shown that heat shock induces rapid dephosphorylation of tau in both female and male rats followed by hyperphosphorylation only in female rats. To investigate the role of gonadal hormones, rats were ovariectomized (OVX), orchiectomized (ORX), or sham-gonadectomized and received replacement therapy with estradiol benzoate (EB), testosterone propionate (TP), or sesame oil (SO) vehicle for 2-3 weeks, respectively. At 0, 3, 6, and 12 hr after heat shock, immunoblot analysis of SDS cerebral extracts was performed using phosphate-dependent and -independent anti-tau antibodies. Seven groups of rats were analyzed: (i) sham-OVX + SO; (ii) OVX + SO; (iii) OVX + EB; (iv) sham-ORX + SO; (v) ORX + SO; (vi) ORX + TP; and (vii) ORX. In all seven groups, there was dephosphorylation of tau at 0 hr after heat shock. In all three groups of female rats, there was hyperphosphorylation of tau at 3 hr after heat shock, and its degree and temporal pattern were identical between the OVX + SO and OVX + EB groups. In male rats, there was hyperphosphorylation of tau at 3 hr after heat shock in both ORX + SO and ORX groups, and its degree was reduced in the ORX + TP group. Thus, dephosphorylation of tau is gonadal hormone-independent, but while its hyperphosphorylation is estrogen-independent it is prevented by androgens. Because tau is abnormally hyperphosphorylated in Alzheimer disease, which is more frequent in women than men, these findings suggest that androgens may exert a neuroprotective effect.