title: Impaired thermoregulation and beneficial effects of thermoneutrality in the 3×Tg-AD model of Alzheimer's disease.
abstract: The sharp rise in the incidence of Alzheimer's disease (AD) at an old age coincides with a reduction in energy metabolism and core body temperature. We found that the triple-transgenic mouse model of AD (3×Tg-AD) spontaneously develops a lower basal body temperature and is more vulnerable to a cold environment compared with age-matched controls. This was despite higher nonshivering thermogenic activity, as evidenced by brown adipose tissue norepinephrine content and uncoupling protein 1 expression. A 24-hour exposure to cold (4 °C) aggravated key neuropathologic markers of AD such as: tau phosphorylation, soluble amyloid beta concentrations, and synaptic protein loss in the cortex of 3×Tg-AD mice. Strikingly, raising the body temperature of aged 3×Tg-AD mice via exposure to a thermoneutral environment improved memory function and reduced amyloid and synaptic pathologies within a week. Our results suggest the presence of a vicious cycle between impaired thermoregulation and AD-like neuropathology, and it is proposed that correcting thermoregulatory deficits might be therapeutic in AD.
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, Québec, Canada; Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, Québec, Canada.
authors.forename: Milene
authors.initials: M
authors.lastname: Vandal
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, NC, USA; Faculté de medicine, Université Laval, Québec, Québec, Canada; Institut universitaire de pneumologie et de cardiologie de Québec, Québec, Québec, Canada.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: White
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, Québec, Canada; Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, Québec, Canada.
authors.forename: Marine
authors.initials: M
authors.lastname: Tournissac
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, Québec, Canada.
authors.forename: Cyntia
authors.initials: C
authors.lastname: Tremblay
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, Québec, Canada; Département de Recherche et Développement, Héma-Québec, Québec, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: St-Amour
authors.affiliation: Faculté de medicine, Université Laval, Québec, Québec, Canada; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: Janelle
authors.initials: J
authors.lastname: Drouin-Ouellet
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, Québec, Canada; Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, Québec, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bousquet
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, Québec, Canada.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Traversy
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, Québec, Canada; Faculté de medicine, Université Laval, Québec, Québec, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
authors.affiliation: Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, Québec, Canada; Faculté de medicine, Université Laval, Québec, Québec, Canada; Institut universitaire de pneumologie et de cardiologie de Québec, Québec, Québec, Canada.
authors.forename: Andre
authors.initials: A
authors.lastname: Marette
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, Québec, Canada; Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, Québec, Canada. Electronic address: frederic.calon@pha.ulaval.ca.
authors.forename: Frederic
authors.initials: F
authors.lastname: Calon
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000502:physiology; D001833:Body Temperature Regulation; D003080:Cold Temperature / Q000009:adverse effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000378:metabolism; D010766:Phosphorylation; D013569:Synapses / Q000473:pathology; D013696:Temperature; D022722:Thermogenesis / Q000502:physiology*; D000071256:Uncoupling Protein 1 / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000071256:Uncoupling Protein 1; D016875:tau Proteins; D009638:Norepinephrine
keywords: 3×Tg-AD; Alzheimer's disease; Cold exposure; Thermogenesis; Thermoneutrality