The Heat Shock-Induced Hyperphosphorylation of τ is Estrogen-Independent and Prevented by Androgens: Implications for Alzheimer Disease

We have shown that heat shock induces rapid dephosphorylation of τ 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-τ 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 τ at 0 hr after heat shock. In all three groups of female rats, there was hyperphosphorylation of τ 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 τ 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 τ is gonadal hormone-independent, but while its hyperphosphorylation is estrogen-independent it is prevented by androgens. Because τ is abnormally hyperphosphorylated in Alzheimer disease, which is more frequent in women than men, these findings suggest that androgens may exert a neuroprotective effect.