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

Abstract

Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition. Oligomerization of Aβ1-42 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 Aβ1-42, Aβ1-40, pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), 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 Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia. Whereas isoflurane and sevoflurane did not affect Aβ1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ1-42-induced spine density attenuation. In the presence of Aβ1-40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ1-42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice. None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ1-42 aggregation, LTP, and spine density.