Dexmedetomidine increases tau phosphorylation under normothermic conditions in vivo and in vitro.

TitleDexmedetomidine increases tau phosphorylation under normothermic conditions in vivo and in vitro.
Publication TypeJournal Article
Year of Publication2015
AuthorsWhittington, RA, Virág, L, Gratuze, M, Petry, FR, Noël, A, Poitras, I, Truchetti, G, Marcouiller, F, Papon, M-A, Khoury, NEl, Wong, K, Bretteville, A, Morin, F, Planel, E
JournalNeurobiol Aging
Volume36
Issue8
Pagination2414-28
Date Published2015 Aug
ISSN1558-1497
KeywordsAdrenergic alpha-2 Receptor Antagonists, Animals, Cells, Cultured, Dexmedetomidine, Dose-Response Relationship, Drug, Hippocampus, Humans, Hypnotics and Sedatives, Hypothermia, Induced, In Vitro Techniques, Infusions, Intravenous, Mice, Inbred C57BL, Phosphorylation, Protein Aggregation, Pathological, Spatial Memory, tau Proteins
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.

DOI10.1016/j.neurobiolaging.2015.05.002
Alternate JournalNeurobiol. Aging
PubMed ID26058840
PubMed Central IDPMC4465078
Grant ListR01 GM101698 / GM / NIGMS NIH HHS / United States
MOP-106423 / / Canadian Institutes of Health Research / Canada
PCN-102993 / / Canadian Institutes of Health Research / Canada
R01GM101698 / GM / NIGMS NIH HHS / United States