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.

全世界每年约有3.129亿患者，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AD在女性中的发生率高于男性。以前的研究已经表明 麻醉剂可促进AD神经发病，包括Tau磷酸化。但不清楚 这些影响是否取决于性别。因此，重要的是要确定依赖性别的“好”， “坏”的麻醉剂，并了解其潜在的机制。与文献一致， 具有低键离解能的化合物是不稳定的，因此可以更容易地与蛋白质相互作用， 初步数据显示异氟烷和七氟烷（具有较低的临床键离解能）， 而不是地氟烷（具有较高的临床键解离能），诱导Tau磷酸化和认知功能 这是一种可以通过雄激素来减弱的损伤。在更新R 01中，我们将确定 临床键离解能的差异是异氟烷和七氟烷的分子基础， 而不是地氟烷，激活GSK 3b，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GSK 3b（ser 9）结合，以防止其 与Tau相互作用，从而减弱麻醉剂诱导的Tau磷酸化，Tau运输， 神经元功能障碍和认知障碍。我们将检验我们的假设，即麻醉剂诱导 通过性别依赖性GSK 3b激活、Tau磷酸化 三个具体目的：（1）评估异氟醚，七氟醚和 地氟烷对睾酮和雌二醇的血液/脑水平、脑磷酸化Tau水平和 老年人（18 - 24个月）、AD转基因（5XFAD）、成人（3个月）和青年（6 日龄）小鼠的两种性别;（2）调查键解离能量为基础的机制，这可能 阐明为什么异氟烷、七氟烷和地氟烷对GSK 3b和 以及睾酮或雌二醇如何减弱这种相互作用; 3）确定体内因果关系 使用雌激素和雄激素受体敲除小鼠的关系和靶向干预等 方法.这项建议旨在调查一个研究不足，但重要的健康问题。预期 结果将：1）确定所谓的性别依赖性的“好”和“坏”麻醉剂影响AD神经发病机制 和认知功能; 2）阐明麻醉神经毒性的新潜在机制;和3） 确定预防和治疗策略。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， 女性与男性），更安全的麻醉实践和更好的AD和老年患者的术后结局。