title: Propofol directly increases tau phosphorylation.
abstract: In Alzheimer's disease (AD) and other tauopathies, the microtubule-associated protein tau can undergo aberrant hyperphosphorylation potentially leading to the development of neurofibrillary pathology. Anesthetics have been previously shown to induce tau hyperphosphorylation through a mechanism involving hypothermia-induced inhibition of protein phosphatase 2A (PP2A) activity. However, the effects of propofol, a common clinically used intravenous anesthetic, on tau phosphorylation under normothermic conditions are unknown. We investigated the effects of a general anesthetic dose of propofol on levels of phosphorylated tau in the mouse hippocampus and cortex under normothermic conditions. Thirty min following the administration of propofol 250 mg/kg i.p., significant increases in tau phosphorylation were observed at the AT8, CP13, and PHF-1 phosphoepitopes in the hippocampus, as well as at AT8, PHF-1, MC6, pS262, and pS422 epitopes in the cortex. However, we did not detect somatodendritic relocalization of tau. In both brain regions, tau hyperphosphorylation persisted at the AT8 epitope 2 h following propofol, although the sedative effects of the drug were no longer evident at this time point. By 6 h following propofol, levels of phosphorylated tau at AT8 returned to control levels. An initial decrease in the activity and expression of PP2A were observed, suggesting that PP2A inhibition is at least partly responsible for the hyperphosphorylation of tau at multiple sites following 30 min of propofol exposure. We also examined tau phosphorylation in SH-SY5Y cells transfected to overexpress human tau. A 1 h exposure to a clinically relevant concentration of propofol in vitro was also associated with tau hyperphosphorylation. These findings suggest that propofol increases tau phosphorylation both in vivo and in vitro under normothermic conditions, and further studies are warranted to determine the impact of this anesthetic on the acceleration of neurofibrillary pathology.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America. raw9@columbia.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Whittington
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: François
authors.initials: F
authors.lastname: Marcouiller
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Papon
authors.forename: Noura B
authors.initials: NB
authors.lastname: El Khoury
authors.forename: Carl
authors.initials: C
authors.lastname: Julien
authors.forename: Françoise
authors.initials: F
authors.lastname: Morin
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
mesh_terms: D018686:Anesthetics, Intravenous; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D006993:Hypnotics and Sedatives; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects*; D015742:Propofol / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D016875:tau Proteins; D015742:Propofol