Alzheimer-like hyperphosphorylation of tau in brains of rats with obesity and type 2 diabetes

Abnormally hyperphosphorylation of tau plays a critical role in the pathogenesis of Alzheimer disease (AD) and type 2 diabetes is a known risk factor of AD. Phosphorylation of tau in type 2 diabetic and obese rats was investigated by Western blots. Tau protein was found to be hyperphosphorylated at several AD-related phophorylation sites. The activity of glycogen synthase kinase 3 beta (GSK-3 beta), a key component of insulin signal transduction pathway and a known tau kinase, was also found to be increased in the brains of both diabetic and obese rats. Intrahippocampal injection of LiCl blocked activation of GSK-3 beta in both groups, but only blocked hyperphosphorylation of tau in the obese rats. In addition, the P-subunit of the hippocampal membrane insulin receptor was found to be reduced in the brains of obese and type 2 diabetic rats. These findings suggest that obese and type 2 diabetes increase the probability of AD by increased insulin resistance and consequent upregulation of GSK-3 beta, which leads to hyperphosphorylation of tau, and that impaired glucose metabolism may also contribute to tau hyperphosphorylation in type 2 diabetes.