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

氙气对阿尔茨海默病的病理生理学具有神经保护作用吗？

基本信息

批准号：
48083334
负责人：
Professor Dr. Gerhard Rammes, Ph.D.
金额：
--
依托单位：
Klinik für Anästhesiologie und Intensivmedizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2007
资助国家：
德国
起止时间：
2006-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/48083334?language=en
关键词：
xenon neuroprotective against pathophysiology Alzheimers

项目摘要

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.

挥发性和静脉内麻醉剂通常用于包括患有阿尔茨海默病（AD）的患者在内的人的全身麻醉。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烷和七氟烷可诱导与AD神经发病机制一致的变化，例如，增加淀粉样前体蛋白（APP）加工和淀粉样β蛋白（Abeta）积累。Abeta 1 -42被认为是致病性最强的形式，并且许多研究已经报道可溶性Abeta 1 -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长时程增强（LTP），这是学习和记忆的细胞相关物。气态麻醉剂氙拮抗NMDA受体的效力较低，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，氙改善了突触毒性的影响，A β 1 -42对LTP。在这个建议中要解决的基本问题是：暴露于氙发挥神经保护作用的病理生理学AD？为了解决这个问题，我们将采用生物物理学，分子和细胞生物学，监测神经元活动和动物行为的方法。大多数先前的研究已经使用Abeta 1 -40或Abeta 1 -42肽进行。然而，最近，其他Abeta物种由于其在AD脑中的丰度、高聚集倾向、稳定性和细胞毒性而作为AD中的可能病原体获得相当大的关注。因此，我们将包括有毒的Abeta种类焦谷氨酸修饰的淀粉样蛋白-（AbetapE 3）和硝化Abeta（3 NTyr 10-Abeta）。总之，本提案旨在揭示氙对Abeta寡聚化和Abeta介导的神经毒性的任何潜在有益机制，并可能成为开发AD患者个体麻醉护理的一步。