title: Deregulation of protein phosphatase 2A and hyperphosphorylation of τ protein following onset of diabetes in NOD mice.
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.
authors.affiliation: Centre Hospitalier de l'Université Laval, Axe Neurosciences, Québec, Canada.
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Papon
authors.forename: Noura B
authors.initials: NB
authors.lastname: El Khoury
authors.forename: François
authors.initials: F
authors.lastname: Marcouiller
authors.forename: Carl
authors.initials: C
authors.lastname: Julien
authors.forename: Françoise
authors.initials: F
authors.lastname: Morin
authors.forename: Alexis
authors.initials: A
authors.lastname: Bretteville
authors.forename: Franck R
authors.initials: FR
authors.lastname: Petry
authors.forename: Simon
authors.initials: S
authors.lastname: Gaudreau
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Amrani
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D007035:Hypothermia; D051379:Mice; D016688:Mice, Inbred NOD; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins; D054648:Protein Phosphatase 2