Is xenon neuroprotective against the pathophysiology of Alzheimers disease? Investigating the interaction with the oligomerization and neurotoxicity of beta-amyloid peptide (Abeta)
Human Cognitive and Systems Neuroscience
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Volatile and intravenous anaesthetics are routinely used for general anaesthesia in humans including patients suffering from AD. Several studies suggest that anaesthesia could be associated with the development and progression of AD e.g. increased amyloid precursor protein (APP) processing and amyloid β protein (Aβ) accumulation. Most of the studies have been conducted using Aβ1-40 or Aβ1-42 peptides. However, also other Aβ species are gaining considerable attention in the pathology of AD. Therefore, we also tested the toxic Aβ species 3NTyr10-Aβ and AβpE3. Aβ1-42 is thought to be the most pathogenic form and numerous studies have reported that soluble Aβ1-42 oligomers impair cognitive function and inhibit long-term potentiation (LTP), a cellular correlate for learning and memory. N-methyl-D-aspartate (NMDA) receptor antagonists, delivered at concentrations which still allow physiological activation, are able to prevent Aβ-induced deficits in LTP. The anaesthetic xenon acts as NMDA receptor antagonist and has been reported to be neuroprotective. In our study, we investigated the interaction of xenon, isoflurane, desflurane and sevoflurane with different Aβ-isoforms regarding Aβ aggregation, synaptic activity, spine density and cognitive performance. Time-resolved fluorescence resonance energy transfer (TR-FRET) and silver staining revealed that isoflurane and sevoflurane did not interfere with Aβ1-42 aggregation whereas xenon even decreased the propensity for Aβ1-42 to aggregate. Xenon, but not isoflurane or sevoflurane, reversed Aβ1-42-induced spine density attenuation therby showing neuroprotective activity. Furthermore, xenon partially restored Aβ1-42- and AbpE3-induced synaptotoxic effects measured by LTP. In the presence of either Aβ species, regarding recovery from anaesthetic-induced reduction of neuronal activity propagation in the trisynaptic hippocampal circuit, monitored by voltage-sensitive dye imaging (VSDI), xenon showed more favourable effects than did isoflurane and sevoflurane removal. We further investigated the influence of xenon, sevoflurane and desflurane on cognitive performance and the amount of methoxy-stained Ab plaques in a mouse model of AD (ArcAb). As expected, ArcAb mice learned the task significantly later than did the control group. Interestingly, neither anesthetic applied affected cognitive performance and plaque burden in ArcAb or control mice. Our presented results show that commonly used anaesthetics may interfere with Aβ-dependent pathophysiology of AD. Interestingly, in contrast to other volatile anaesthetics, xenon showed beneficial effects at least on Aβ aggregation and on synaptic activity when experimental conditions resemble the clinical situation with patients suffering from AD and requiring anaesthesia for surgery. In an advanced AD state anaesthesia was not associated with a deterioration of the disease. Our results point to neuroprotective properties of xenon which might be a meaningful alternative for anaesthesia in AD patients.
Publications
- (2019). The anaesthetic xenon partially restores an amyloid beta-induced impairment in murine hippocampal synaptic plasticity. Neuropharmacology 151: 21-32
Bürge, M., et al.
(See online at https://doi.org/10.1016/j.neuropharm.2019.03.031)
