Deregulation of Protein Phosphatase 2A and Hyperphosphorylation of τ Protein Following Onset of Diabetes in NOD Mice

The histopathological hallmarks of Alzheimer disease (AD) include intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein. Insulin dysfunction might influence AD pathology, as population-based and cohort studies have detected higher AD incidence rates in diabetic patients. But how diabetes affects tau pathology is not fully understood. In this study, we investigated the impact of insulin dysfunction on tau phosphorylation in a genetic model of spontaneous type 1 diabetes: the nonobese diabetic (NOD) mouse. Brains of young and adult female NOD mice were examined, but young NOD mice did not display tau hyperphosphorylation. tau phosphorylation at tau-1 and pS422 epitopes was slightly increased in nondiabelic adult NOD mice. At the onset of diabetes, tau was hyperphosphorylated at the tau-1, AT8, CP13, pS262, and pS422. A subpopulation of diabetic NOD mice became hypothermic, and tau hyperphosphorylation further extended to paired helical filament-1 and TG3 epitopes. Furthermore, elevated tau phosphorylation correlated with an inhibition of protein phosphatase 2A (PP2A) activity. Our data indicate that insulin dysfunction in NOD mice leads to AD-like tau hyperphosphorylation in the brain, with molecular mechanisms likely involving a deregulation of PP2A. This model may be a useful tool to address further mechanistic association between insulin dysfunction and AD pathology. Diabetes 62:609-617, 2013