title: Hypothermia mediates age-dependent increase of tau phosphorylation in db/db mice.
abstract: Accumulating evidence from epidemiological studies suggest that type 2 diabetes is linked to an increased risk of Alzheimer's disease (AD). However, the consequences of type 2 diabetes on AD pathologies, such as tau hyperphosphorylation, are not well understood. Here, we evaluated the impact of type 2 diabetes on tau phosphorylation in db/db diabetic mice aged 4 and 26weeks. We found increased tau phosphorylation at the CP13 epitope correlating with a deregulation of c-Jun. N-terminal kinase (JNK) and Protein Phosphatase 2A (PP2A) in 4-week-old db/db mice. 26-week-old db/db mice displayed tau hyperphosphorylation at multiple epitopes (CP13, AT8, PHF-1), but no obvious change in kinases or phosphatases, no cleavage of tau, and no deregulation of central insulin signaling pathways. In contrast to younger animals, 26-week-old db/db mice were hypothermic and restoration of normothermia rescued phosphorylation at most epitopes. Our results suggest that, at early stages of type 2 diabetes, changes in tau phosphorylation may be due to deregulation of JNK and PP2A, while at later stages hyperphosphorylation is mostly a consequence of hypothermia. These results provide a novel link between diabetes and tau pathology, and underlie the importance of recording body temperature to better understand the relationship between diabetes and AD.
authors.affiliation: Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Noura B
authors.initials: NB
authors.lastname: El Khoury
authors.affiliation: Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Maud
authors.initials: M
authors.lastname: Gratuze
authors.affiliation: Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Franck
authors.initials: F
authors.lastname: Petry
authors.affiliation: Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Papon
authors.affiliation: Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Julien
authors.affiliation: Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Marcouiller
authors.affiliation: Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Françoise
authors.initials: F
authors.lastname: Morin
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Samantha B
authors.initials: SB
authors.lastname: Nicholls
authors.affiliation: Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada; Université Laval, Faculté de Pharmacie, Québec, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
authors.affiliation: Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.affiliation: Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada; Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada. Electronic address: emmanuel@planel.org.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
mesh_terms: D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D038321:Glycemic Index; D007036:Hypothermia, Induced; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D020738:Leptin; D016875:tau Proteins; D048670:MAP Kinase Kinase 4
keywords: Alzheimer's disease; Diabetes mellitus; Hippocampus; Hypothermia; Kinase; Phosphatase; Tau hyperphosphorylation; Temperature; Thermoregulation; db/db mice