title: Insulin deprivation induces PP2A inhibition and tau hyperphosphorylation in hTau mice, a model of Alzheimer's disease-like tau pathology.
abstract: Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer's disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas. One high dose of STZ resulted in marked diabetes, and five low doses led to a milder diabetes. Both groups exhibited brain tau hyperphosphorylation but no increased aggregation. Tau hyperphosphorylation correlated with inhibition of Protein Phosphatase 2A (PP2A), the main tau phosphatase. Interestingly, insulin injection 30 minutes before sacrifice partially restored tau phosphorylation to control levels in both STZ-injected groups. Our results confirm a link between insulin homeostasis and tau phosphorylation, which could explain, at least in part, a higher incidence of AD in diabetic patients.
authors.affiliation: Université Laval, Faculté de médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada.|Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Maud
authors.initials: M
authors.lastname: Gratuze
authors.affiliation: Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Jacinthe
authors.initials: J
authors.lastname: Julien
authors.affiliation: Université Laval, Faculté de médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada.|Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Franck R
authors.initials: FR
authors.lastname: Petry
authors.affiliation: Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Françoise
authors.initials: F
authors.lastname: Morin
authors.affiliation: Université Laval, Faculté de médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada.|Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D024801:Tauopathies / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D054648:Protein Phosphatase 2