Is xenon neuroprotective against the pathophysiology of Alzheimers disease? Investigating the interaction with the oligomerization and neurotoxicity of beta-amyloid peptide (Abeta)

点击翻译按钮获取中文摘要

Volatile and intravenous anesthetics are routinely used for general anesthesia in humans including patients suffering from Alzheimer's disease (AD). Several studies suggest that anesthesia could be associated with the development and progression of AD. Moreover, studies in cultured cells and animals show that commonly used inhalation anesthetics such as isoflurane and sevoflurane may induce changes consistent with AD neuropathogenesis, e.g., increased amyloid precursor protein (APP) processing and amyloid beta protein (Abeta) accumulation. Abeta1-42 is thought to be the most pathogenic form and numerous studies have reported that soluble Abeta1-42 oligomers affect N-methyl-D-aspartate (NMDA) receptor function, impair cognitive function and inhibit long-term potentiation (LTP), a cellular correlate for learning and memory. The gaseous anesthetic xenon antagonizes NMDA receptors with low potency and has frequently been reported to be neuroprotective against cerebral damage. Interestingly, our preliminary experiments showed that xenon ameliorates the synaptotoxic effects of Abeta1-42 on LTP. The fundamental question to be addressed in this proposal is: Does exposure to xenon exert neuroprotective effects in the pathophysiology of AD? To address this question, we will employ methods from biophysics, molecular and cell biology, monitoring neuronal activity and animal behaviour. Most previous studies have been conducted using Abeta1-40 or Abeta1-42 peptides. However, recently other Abeta species are gaining considerable attention as possible pathogens in AD due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Therefore, we will include the toxic Abeta species pyroglutamate-modified amyloid-(AbetapE3) and nitrated Abeta (3NTyr10-Abeta). Altogether, the present proposal intends to reveal any potential beneficial mechanisms of xenon regarding Abeta oligomerization and Abeta-mediated neurotoxicity and might be a step towards the development of an individual anaesthesia care for AD patients.