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

挥发性麻醉剂和静脉麻醉剂通常用于人类全身麻醉，包括阿尔茨海默病(AD)患者。一些研究表明，麻醉可能与AD的发展和进展有关。此外，在培养的细胞和动物中的研究表明，常用的吸入麻醉剂，如异氟醚和七氟烷，可能会引起与AD神经发病机制一致的变化，例如，淀粉样前体蛋白(APP)加工增加和淀粉样β蛋白(Abeta)积聚。Abeta1-42被认为是最具致病性的形式，许多研究报道了可溶性Abeta1-42寡聚体影响N-甲基-D-天冬氨酸(NMDA)受体功能，损害认知功能，并抑制与学习和记忆相关的细胞长时程增强(LTP)。气体麻醉剂氙气以低效拮抗NMDA受体，并经常被报道对脑损伤具有神经保护作用。有趣的是，我们的初步实验表明，氙气可以改善Abeta1-42对LTP的突触毒性效应。这项建议要解决的基本问题是：暴露在氙气中是否在AD的病理生理中起到神经保护作用？为了解决这个问题，我们将使用生物物理学、分子和细胞生物学的方法，监测神经元活动和动物行为。以前的大多数研究都是使用Abeta1-40或Abeta1-42多肽进行的。然而，近年来，其他Abeta物种因其在AD脑中的丰度、高聚集倾向、稳定性和细胞毒性而作为可能的AD病原体而受到相当大的关注。因此，我们将包括有毒的Abeta物种焦谷氨酸修饰的淀粉样蛋白(AbetapE3)和硝酸Abeta(3NTyr10-Abeta)。综上所述，本提案旨在揭示氙气在Abeta齐聚和Abeta介导的神经毒性方面的任何潜在的有益机制，并可能是朝着发展AD患者的个体化麻醉护理的方向迈出的一步。

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.