Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia.
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
Emmanuel
E
Axe Neurosciences, Centre Hospitalier de l'Université Laval, Université Laval, Québec, Québec, Canada.
Bretteville
Alexis
A
Liu
Li
L
Virag
Laszlo
L
Du
Angela L
AL
Yu
Wai Haung
WH
Dickson
Dennis W
DW
Whittington
Robert A
RA
Duff
Karen E
KE
D000544:Alzheimer Disease / Q000209:etiology; D000769:Anesthesia, Inhalation / Q000009:adverse effects*; D018685:Anesthetics, Inhalation / Q000633:toxicity; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007530:Isoflurane / Q000633:toxicity; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D009048:Motor Skills; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D018685:Anesthetics, Inhalation; D016875:tau Proteins; D007530:Isoflurane; D000071679:Glycogen Synthase Kinase 3 beta; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D038362:Glycogen Synthase Kinase 3