Inhalational Anesthetics Do Not Deteriorate Amyloid-beta-Derived Pathophysiology in Alzheimer's Disease: Investigations on the Molecular, Neuronal, and Behavioral Level

Background: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-beta (A beta) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. Objective: In the present study, we want to detail the interactions of inhalational anesthetics with A beta-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding A beta oligomerization and A beta-mediated neurotoxicity on processes related to cognition. Methods: Oligomerization of A beta(1-42) in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and A beta(1-42), A beta(1-40), pyroglutamate-modified amyloid-(A beta pE3), and nitrated A beta (3NTyrA beta), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and A beta plaque burden in transgenic AD mice (ArcA beta) after anesthesia. Results: Whereas isoflurane and sevoflurane did not affect A beta(1-42) aggregation, xenon alleviated the propensity for aggregation and partially reversed A beta pE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed A beta(1-42)-induced spine density attenuation. In the presence of A beta(1-40) and A beta pE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with A beta(1-42) or 3NTyrA beta, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcA beta mice. Conclusion: None of the anesthetics aggravated A beta-derived AD pathology in vivo. However, A beta and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on A beta(1-42) aggregation, LTP, and spine density.