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Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia

Emmanuel Planel^*,,, Alexis Bretteville, Li Liu, Laszlo Virag, Angela L. Du, Wai Haung Yu, Dennis W. Dickson^||, Robert A. Whittington and Karen E. Duff^,,1

^* Axe Neurosciences, Centre Hospitalier de l’Université Laval—Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Québec, Canada;

Department of Pathology, Taub Institute for Alzheimer’s Disease Research, and

Department of Anesthesiology, Columbia University Medical Center, New York, New York, USA;

Department of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York, USA; and

^|| Department of Pathology and Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, USA

¹ Correspondence: Columbia University Medical Center, Department of Pathology, Taub Institute for Alzheimer’s Disease Research, P&S Bldg. 12-461, 630 West 168th St., New York, NY 10032, USA. E-mail: ked2115{at}columbia.edu

Alzheimer’s disease and other tauopathies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer’s disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long-term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points—during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho-tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho-tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia-induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.—Planel, E., Bretteville, A., Liu, L., Virag, L., Du, A. L., Yu, W. Y., Dickson, D. W., Whittington, R. A., Duff, K. E. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia.

Key Words: Alzheimer’s disease • hypothermia • tau hyperphosphorylation • microtubules

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