Journal
NEUROBIOLOGY OF AGING
Volume 36, Issue 8, Pages 2414-2428Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2015.05.002
Keywords
Dexmedetomidine; Anesthesia; Tau; Alzheimer's disease; Mouse; Cells
Categories
Funding
- National Institutes of Health [R01GM101698]
- Canadian Institute of Health Research [MOP-106423, PCN-102993]
- Fonds de Recherche en Sante du Quebec [16205, 20048]
- Natural Sciences and Engineering Research Council of Canada [354722]
- Alzheimer Society of Canada
- Alzheimer Society of Canada Biomedical Award
- Didier Mouginot Doctoral Award
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM101698] Funding Source: NIH RePORTER
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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 a2-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 a2-adrenergic receptor activation, (2) promotes tau aggregation in a mouse model of tauopathy, and (3) impacts spatial reference memory. (C) 2015 Elsevier Inc. All rights reserved.
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