title: Dexmedetomidine increases tau phosphorylation under normothermic conditions in vivo and in vitro.
abstract: There is developing interest in the potential association between anesthesia and the onset and progression of Alzheimer's disease. Several anesthetics have, thus, been demonstrated to induce tau hyperphosphorylation, an effect mostly mediated by anesthesia-induced hypothermia. Here, we tested the hypothesis that acute normothermic administration of dexmedetomidine (Dex), an intravenous sedative used in intensive care units, would result in tau hyperphosphorylation in vivo and in vitro. When administered to nontransgenic mice, Dex-induced tau hyperphosphorylation persisting up to 6 hours in the hippocampus for the AT8 epitope. Pretreatment with atipamezole, a highly specific α2-adrenergic receptor antagonist, blocked Dex-induced tau hyperphosphorylation. Furthermore, Dex dose-dependently increased tau phosphorylation at AT8 in SH-SY5Y cells, impaired mice spatial memory in the Barnes maze and promoted tau hyperphosphorylation and aggregation in transgenic hTau mice. These findings suggest that Dex: (1) increases tau phosphorylation, in vivo and in vitro, in the absence of anesthetic-induced hypothermia and through α2-adrenergic receptor activation, (2) promotes tau aggregation in a mouse model of tauopathy, and (3) impacts spatial reference memory.
authors.affiliation: Department of Anesthesiology, Columbia University, College of Physicians and Surgeons, New York, NY, USA. Electronic address: raw9@cumc.columbia.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Whittington
authors.affiliation: Department of Anesthesiology, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Maud
authors.initials: M
authors.lastname: Gratuze
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Franck R
authors.initials: FR
authors.lastname: Petry
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Noël
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Poitras
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Truchetti
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Marcouiller
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Papon
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Noura
authors.initials: N
authors.lastname: El Khoury
authors.affiliation: Department of Anesthesiology, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wong
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Alexis
authors.initials: A
authors.lastname: Bretteville
authors.affiliation: Neurosciences, CHUL, CRCHU, Québec, Québec, Canada.
authors.forename: Françoise
authors.initials: F
authors.lastname: Morin
authors.affiliation: Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Québec, Canada; Neurosciences, CHUL, CRCHU, Québec, Québec, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects*; D007036:Hypothermia, Induced; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000139:chemically induced; D065852:Spatial Memory / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D006993:Hypnotics and Sedatives; D016875:tau Proteins; D020927:Dexmedetomidine
keywords: Alzheimer's disease; Anesthesia; Cells; Dexmedetomidine; Mouse; Tau