General Anesthesia and Alzheimer's Disease Neuropathogenesis

世界各地每年约有3.129亿名患者，其中约850万人 阿尔茨海默病(AD)患者和更多易患AD的老年患者需要 麻醉下的手术。广告在女性中的发生率高于男性。此前的研究表明， 麻醉药可促进AD的神经发病，包括Tau的磷酸化。然而，它是未知的 这些影响是否取决于性别。因此，重要的是要确定与性别有关的“好的”和 “坏”麻醉剂，并了解其潜在的机制。与文献中提到的 具有低键离解能的化合物是不稳定的，因此更容易与蛋白质相互作用，我们的 初步数据显示，异氟醚和七氟烷(临床结合解离能较低)， 而不是地氟烷(具有较高的临床结合解离能)，诱导Tau磷酸化和认知 损害，这可以通过雄激素来减轻。在更新R01中，我们将确定是否 临床键离能差异是异氟醚和七氟醚的分子基础，但 不是地氟烷，而是激活GSK3b，即Tau磷酸化的激酶。此外，我们将决定是否 睾酮(雄激素)和雌二醇(雌激素)可以与磷酸化的GSK3b(Ser9)结合，以阻止其 与Tau相互作用，从而减弱麻醉诱导的Tau磷酸化，Tau转运， 神经功能障碍和认知障碍。我们将检验我们的假设，即麻醉剂会导致更严重的 性别依赖性GSK3b激活Tau磷酸化对雌性小鼠认知功能的损害 和神经元功能障碍在三个特定的目的：(1)评估异氟醚，七氟醚和 地氟醚对血/脑组织睾酮和雌二醇水平、脑内磷酸化牛磺酸水平和 老年(18-24个月)、AD转基因(5XFAD)、成人(3个月大)和年轻(6个月)的认知功能 天大的)小鼠；(2)研究一种基于键离解能的机制，这可能 异氟醚、七氟烷和地氟烷对GSK3b和GSK3b相互作用的不同影响 以及睾丸激素或雌二醇如何减弱这种相互作用；3)确定体内的因果关系 利用雌激素和雄激素受体基因敲除小鼠等的关系和靶向干预 方法：研究方法。这项提议旨在调查一个未得到充分研究但却很重要的健康话题。预期中的 结果将：1)确定所谓的性别依赖的“好”和“坏”麻醉剂影响阿尔茨海默病神经发病 和小鼠的认知功能；2)阐明麻醉神经毒性的新潜在机制；以及3) 确定防治策略。这些调查，包括性别差异 研究，将在概念上推进麻醉神经毒性的研究，并促进更多的研究， 包括临床研究，并最终导致个性化麻醉护理的发展(例如， 对于AD和老年患者来说，更安全的麻醉实践和更好的术后结果。

Each year around the world, there are about 312.9 million patients, including approximate 8.5 million Alzheimer’s disease (AD) patients and a greater number of senior patients who are vulnerable to AD that need surgery under anesthesia. AD occurs more often in women than in men. Previous studies have shown that anesthetics can promote AD neuropathogenesis, including Tau phosphorylation. However, it is unknown whether or not these effects are dependent on sex. Thus, it is important to identify sex-dependent “good” and “bad” anesthetics and to understand their underlying mechanisms. Consistent with the literature that compounds with low bond-dissociation energy are unstable and thus can more easily interact with proteins, our preliminary data have shown that isoflurane and sevoflurane (with a lower clinical bond-dissociation energy), but not desflurane (with a higher clinical bond-dissociation energy), induce Tau phosphorylation and cognitive impairment, which can be attenuated by androgen. In the renewal R01, we will determine whether or not the difference in clinical bond-dissociation energy is the molecular basis by which isoflurane and sevoflurane, but not desflurane, activate GSK3b, the kinase for Tau phosphorylation. Moreover, we will decide whether testosterone (androgen) and estradiol (estrogen) can bind to phosphorylated GSK3b(ser9) to prevent its interaction with Tau and thus to attenuate the anesthetic-induced Tau phosphorylation, Tau trafficking, neuronal dysfunction and cognitive impairment. We will test our hypothesis that anesthetics induce severer cognitive impairments in female mice through a sex-dependent GSK3b activation, Tau phosphorylation and neuronal dysfunction in three Specific Aims: (1) assess the effects of isoflurane, sevoflurane and desflurane on the blood/brain levels of testosterone and estradiol, brain phosphorylated Tau levels and cognitive function in aging (18 - 24 months old), AD transgenic (5XFAD), adult (3 months old) and young (6 days old) mice of both genders; (2) investigate a bond-dissociation energy-based mechanism, which may elucidate why isoflurane, sevoflurane and desflurane have different effects on the interaction of GSK3b and Tau; and how testosterone or estradiol attenuate such interaction; 3) determine the in vivo cause-effect relationship and targeted interventions using estrogen and androgen receptor knockout mice among other methods. This proposal aims at investigating an understudied, yet important health topic. The anticipated results would: 1) identify so called sex-dependent “good” and “bad” anesthetic affecting AD neuropathogenesis and cognitive function in mice; 2) elucidate new underlying mechanisms of anesthesia neurotoxicity; and 3) determine the strategies of prevention and treatment. These investigations, including the gender difference studies, would conceptually advance the research on anesthesia neurotoxicity and promote more studies, including clinical investigations, and ultimately lead to the development of personalized anesthesia care (e.g., women vs. men), safer anesthesia practice and better postoperative outcomes for AD and senior patients.