Inhalational Anesthetics Do Not Deteriorate Amyloid-β-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.

Automated summary

The study found that xenon has a slowing effect on Aβ aggregation, as well as positive impacts on LTP and spine density. Isoflurane and sevoflurane did not exacerbate the AD pathology caused by Aβ, but they did impact neuronal activity in vitro.