title: Tau hyperphosphorylation in the brain of ob/ob mice is due to hypothermia: Importance of thermoregulation in linking diabetes and Alzheimer's disease.
abstract: Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM. Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1). We then examined the mechanism of tau hyperphosphorylation and demonstrated that it is mostly due to hypothermia, as ob/ob mice were hypothermic and normothermia restored tau phosphorylation to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and tau phosphorylation, we, therefore, used it as therapeutic treatment. Unexpectedly, chronic caffeine intake exacerbated tau hyperphosphorylation by promoting deeper hypothermia. Our data indicate that tau hyperphosphorylation is predominately due to hypothermia consequent to impaired thermoregulation in ob/ob mice. This study establishes a novel link between diabetes and AD, and reinforces the importance of recording body temperature to better assess the relationship between diabetes and AD.
authors: 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: Maud
authors: M
authors: Gratuze
authors: 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: Noura B
authors: NB
authors: El Khoury
authors: 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: Andréanne
authors: A
authors: Turgeon
authors: Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors: Carl
authors: C
authors: Julien
authors: 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: François
authors: F
authors: Marcouiller
authors: Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada.
authors: Françoise
authors: F
authors: Morin
authors: Columbia University Medical Center, Department of Anesthesiology, New York, NY, USA.
authors: Robert A
authors: RA
authors: Whittington
authors: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC, Canada.
authors: André
authors: A
authors: Marette
authors: Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada; Université Laval, Faculté de Pharmacie, Québec, QC, Canada.
authors: Frédéric
authors: F
authors: Calon
authors: 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: Emmanuel
authors: E
authors: Planel
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology; D002110:Caffeine / Q000633:toxicity; D000697:Central Nervous System Stimulants / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007035:Hypothermia / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D020738:Leptin; C558298:Mapt protein, mouse; D016875:tau Proteins; D002110:Caffeine
keywords: Alzheimer's disease; Caffeine; Diabetes mellitus; Hypothermia; Kinase; Leptin; Phosphatase; Tau hyperphosphorylation, hippocampus; Temperature; Thermoregulation; ob/ob mice