Rosiglitazone ameliorate Alzheimer-like hyperphosphorylation of tau protein in the hippocampus of rats with insulin resistance

Abnormally hyperphosphorylation of tau plays a critical role in the pathogenesis of Alzheimer disease (AD). Type 2 diabetes whose character is insulin resistance is a known factor of AD. Tau protein were found to be hyperphosphorylated at several AD-related phosphorylation sites (Ser199, Thr212, Ser214, Ser396 and Ser422) in insulin resistant rats. TZD treatment reduced hyperphosphorylation of Ser199, Thr212, Ser396 and Ser422 of tau significantly and of Ser214 of tau to the control level. The activity of GSK-3 beta was found to be increased dramatically in the hippocampi before and after TZD treatment. These findings suggest (1) that insulin resistance induced by obesity causes a downregulation of insulin signal transduction and the consequent upregulation of GSK-3 beta activity, which leads to hyperphosphorylation of tau protein, and (2) that rosiglitazone can partially reverse insulin resistance induced tau hyperphosphorylation, which may not mediated by inhibition of GSK-3 beta activity.