Deregulation of protein phosphatase 2A and hyperphosphorylation of [tau] protein following onset of diabetes in NOD mice.(ORIGINAL ARTICLE)

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 diabet...

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Published inDiabetes (New York, N.Y.) Vol. 62; no. 2; p. 609
Main Authors Papon, Marie-Amelie, El Khoury, Noura B, Marcouiller, Francois, Julien, Carl, Morin, Francoise, Bretteville, Alexis, Petry, Franck R, Gaudreau, Simon, Amrani, Abdelaziz, Mathews, Paul M, Hebert, Sebastien S, Planel, Emmanuel
Format Journal Article
LanguageEnglish
Published New York American Diabetes Association 01.02.2013
Subjects
Alzheimer's disease
Animals
Brain research
Cohort analysis
Development and progression
Diabetes
Diabetes mellitus
Glucose
Health aspects
Insulin
Laboratories
Medical research
Pathology
Phosphatase
Phosphatases
Phosphorylation
Physiological aspects
Physiology
Proteins
Software
United States
Germany
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Summary: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 nondiabetic 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 timber mechanistic association between insulin dysfunction and AD pathology. Diabetes 62:609-617, 2013
ISSN:0012-1797
1939-327X
DOI:10.2337/db12-0187