Deregulation of protein phosphatase 2A and hyperphosphorylation of τ protein following onset of diabetes in NOD mice.

TitleDeregulation of protein phosphatase 2A and hyperphosphorylation of τ protein following onset of diabetes in NOD mice.
Publication TypeJournal Article
Year of Publication2013
AuteursPapon, M-A, Khoury, NBEl, Marcouiller, F, Julien, C, Morin, F, Bretteville, A, Petry, FR, Gaudreau, S, Amrani, A, Mathews, PM, Hébert, SS, Planel, E
JournalDiabetes
Volume62
Issue2
Pagination609-17
Date Published2013 Feb
ISSN1939-327X
KeywordsAlzheimer Disease, Animals, Brain, Brain Chemistry, Diabetes Mellitus, Type 1, Disease Models, Animal, Female, Hypothermia, Mice, Mice, Inbred NOD, Neurofibrillary Tangles, Phosphorylation, Protein Isoforms, Protein Phosphatase 2, tau Proteins
Abstract

The histopathological hallmarks of Alzheimer disease (AD) include intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated τ 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 τ pathology is not fully understood. In this study, we investigated the impact of insulin dysfunction on τ 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 τ hyperphosphorylation. τ phosphorylation at τ-1 and pS422 epitopes was slightly increased in nondiabetic adult NOD mice. At the onset of diabetes, τ was hyperphosphorylated at the τ-1, AT8, CP13, pS262, and pS422. A subpopulation of diabetic NOD mice became hypothermic, and τ hyperphosphorylation further extended to paired helical filament-1 and TG3 epitopes. Furthermore, elevated τ phosphorylation correlated with an inhibition of protein phosphatase 2A (PP2A) activity. Our data indicate that insulin dysfunction in NOD mice leads to AD-like τ 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.

DOI10.2337/db12-0187
Alternate JournalDiabetes
PubMed ID22961084
PubMed Central IDPMC3554372
Grant ListMOP-106423 / / Canadian Institutes of Health Research / Canada
PCN-102993 / / Canadian Institutes of Health Research / Canada