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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

全球每年约有 3.129 亿患者，其中约 850 万人阿尔茨海默病 (AD) 患者和大量易患 AD 的老年患者需要先前的研究表明，麻醉下手术在女性中更常见。麻醉剂可促进 AD 神经发病，包括 Tau 磷酸化，但目前尚不清楚。这些影响是否取决于性别因此，重要的是要确定性别依赖性的“好”和“好”。 “坏”麻醉剂并了解其潜在机制与文献一致。具有低键解离能的化合物不稳定，因此更容易与蛋白质相互作用，我们的初步数据表明，异氟烷和七氟烷（临床键解离能较低），但地氟烷（具有较高的临床键解离能）不会诱导 Tau 磷酸化和认知能力在更新 R01 中，我们将确定是否会因雄激素而减弱。临床键解离能的差异是异氟烷和七氟烷的分子基础，但是不是地氟烷，激活 Tau 磷酸化激酶 GSK3b 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，以防止其发生。与 Tau 相互作用，从而减弱麻醉诱导的 Tau 磷酸化、Tau 转运，我们将检验麻醉剂会导致更严重的神经元功能障碍和认知障碍的假设。通过性别依赖性 GSK3b 激活、Tau 磷酸化导致雌性小鼠认知障碍和神经元功能障碍的三个具体目标：（1）评估异氟烷、七氟烷和地氟烷对血液/大脑中睾酮和雌二醇水平、大脑磷酸化 Tau 水平和衰老（18 - 24 个月大）、AD 转基因（5XFAD）、成人（3 个月大）和年轻人（6 (2) 研究基于键解离能的机制，这可能阐明为什么异氟醚、七氟醚和地氟醚对 GSK3b 和 GSK3b 的相互作用有不同的影响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等进行的关系和针对性干预该提案旨在调查一个尚未得到充分研究但很重要的健康主题。结果将：1) 确定影响 AD 神经发病机制的所谓性别依赖性“好”和“坏”麻醉剂和小鼠的认知功能；2）阐明麻醉神经毒性的新潜在机制；确定预防和治疗策略，包括性别差异。研究，将从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），为 AD 和老年患者提供更安全的麻醉实践和更好的术后结果。