General Anesthesia and Alzheimer's Disease Neuropathogenesis

全身麻醉与阿尔茨海默病的神经发病机制

• 批准号: 10119369
• 负责人: Zhongcong Xie
• 金额: $ 191.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10119369
• 关键词: AD transgenic mice; Adult; Affect; Age; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s neuropathogenesis; Androgen Receptor; Androgens; Anesthesia procedures; Anesthetics; Attenuated; Binding; Blood; Brain; Caring; Cells; Clinical; Cognition; Data; Development; Dissociation; Electrophysiology (science); Estradiol; Estrogen Receptors; Estrogens; Female; Functional disorder; Gender; General Anesthesia; Genetic; Glycine; Goals; Gonadal Steroid Hormones; Health; Impaired cognition; In Vitro; Intervention; Investigation; Isoflurane; Kinetics; Knockout Mice; Lead; Literature; Long-Term Potentiation; Longevity; Measures; Methods; Molecular; Mus; Nanotechnology; Neurocognitive; Neuronal Dysfunction; Neurons; Operative Surgical Procedures; Orchiectomy; Outcome; Ovariectomy; Patients; Pharmacology; Postoperative Period; Prevention strategy; Proteins; RNA Interference; Reporting; Research; System; Testing; Testosterone; Time; Transgenic Organisms; United States National Institutes of Health; Woman; base; clinical investigation; cognitive function; desflurane; gender difference; in vivo; innovation; knock-down; male; men; mouse model; nanoprobe; neuroprotection; neurotoxic; neurotoxicity; novel; older patient; postsynaptic; prevent; real time monitoring; reproductive; sevoflurane; sex; tau Proteins; tau phosphorylation; tau-1; tau-protein kinase; trafficking

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.

全球每年，大约有3.1290万患者，其中包括850万人 阿尔茨海默氏病（AD）患者和易于受到广告的高级患者的数量 在麻醉下进行手术。广告在女性中的发生频率比男性更频繁。先前的研究表明 麻醉药可以促进AD神经病发生，包括tau磷酸化。但是，这是未知的 这些影响是否取决于性。这一点很重要 “坏”麻醉剂并了解其潜在机制。与文学一致 低键分解能的化合物不稳定，因此可以更容易与蛋白质相互作用，我们 初步数据表明，异氟烷和七氟硫烷（具有较低的临床键 - 分解能）， 但不是desflurane（具有较高的临床键 - 分解能），诱导tau磷酸化和认知能力 损伤，可以通过雄激素减弱。在续签R01中，我们将确定是否确定 临床键分解能量的差异是分子基础，这些基础是异氟烷和七氟醚，但 不是Desflurane，激活GSK3B，是tau磷酸化的激酶。而且，我们将决定是否 睾丸激素（雄激素）和雌二醇（雌激素）可以与磷酸化的GSK3B（Ser9）结合以防止其 与tau相互作用，从而减弱麻醉诱导的tau磷酸化，tau贩运， 神经元功能障碍和认知障碍。我们将检验我们的假设，即麻醉药会影响几种 通过性依赖性GSK3B激活，tau磷酸化的雌性小鼠认知障碍 和三个特定目的的神经元功能障碍：（1）评估异氟烷，七氟醚和 睾丸激素和雌二醇的血液/脑水平上的氟烷，脑磷酸化的tau水平和 衰老的认知功能（18-24个月大），AD转基因（5xFAD），成人（3个月大）和年轻（6 几天）两种性别的小鼠； （2）研究基于键的能量机制，可能 阐明为什么异氟烷，七氟醚和desflurane对GSK3B的相互作用有不同的影响 tau;以及睾丸激素或雌二醇如何减弱这种相互作用； 3）确定体内原因效应 使用雌激素和雄激素受体基因敲除小鼠的关系和靶向干预措施 方法。该建议旨在调查一个理解但重要的健康主题。预期 结果将：1）确定所谓的性别依赖性的“好”和“坏”麻醉影响AD神经病发生 小鼠的认知功能； 2）阐明麻醉神经毒性的新基本机制； 3） 确定预防和治疗的策略。这些调查，包括性别差异 研究将在概念上提高有关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， 女性与男性），安全的麻醉练习以及对AD和高级患者的后果后果更好。