Anesthetics and Alzheimer's Disease

麻醉药和阿尔茨海默病

• 批准号: 7663949
• 负责人: Roderic G Eckenhoff
• 金额: $ 32.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663949
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Anesthesia procedures; Anesthetics; Animal Model; Animals; Antibodies; Apoptotic; Appearance; Behavior; Biochemical; Brain; Breathing; Caring; Cell Death; Cognition; Cognitive; Cognitive deficits; Disease; Dose; Drug Exposure; Drug usage; Early Diagnosis; Elderly; Environment; Evaluation; Exposure to; Floor; Functional disorder; General anesthetic drugs; Halothane; Hippocampus (Brain); Histopathology; Human; Immunoblotting; Immunohistochemistry; Immunotherapeutic agent; Impaired cognition; In Vitro; Injectable; Inositol; Isoflurane; Learning; Lesion; Life; Life Expectancy; Link; Measurement; Memory; Molecular; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurocognitive; Neurofibrillary Tangles; Outcome; Pathogenesis; Pathology; Patients; Pentobarbital; Peptides; Perioperative Care; Pharmaceutical Preparations; Phase; Phenotype; Play; Procedures; Production; Propofol; Proteins; Public Health; Reporting; Role; Sampling; Solubility; Symptoms; Synapses; Synaptophysin; Testing; Tg2576; Time; Transgenes; Transgenic Mice; Translations; abeta accumulation; caspase-3; cytotoxicity; desflurane; design; extracellular; hyperphosphorylated tau; mild neurocognitive impairment; monomer; morris water maze; mouse model; neuropathology; public health relevance; response; sevoflurane; small molecule; synaptotagmin; syntaxin; tau Proteins; tau expression; tau phosphorylation

DESCRIPTION (provided by applicant): Inhaled anesthetics increase the aggregation of amyloid beta in vitro through the stabilization of intermediate oligomers, a species thought to cause neurocognitive dysfunction in Alzheimer's disease (AD). Others have reported that production of amyloid beta is also increased. Thus, inhaled anesthetics may contribute to diminished cognition by increasing the brain concentration of amyloid beta in a toxic form. We have found that anesthetics enhanced plaque load in Tg2576 transgenic mice (a model of AD), but produced no incremental cognitive deficit. We suspect this is due to either a floor effect or insufficient time for the new neuropathology to produce cognitive decline. We now propose to expand these studies in a more recent animal model with 3 transgenes, involving several molecular steps in AD pathogenesis. We will determine the interaction between anesthetics and AD by exposing these animals to five different anesthetics at various ages to address the hypothesis that the anesthetic enhances the rate of amyloid and tau histopathology and cognitive decline, and that a specific window of vulnerability exists. In addition, the levels of the small amyloid beta oligomers, hyperphosphorylated tau, caspase-3 and synaptic markers will be biochemically quantitated after anesthetic exposures in order to test our mechanistic hypothesis. We will also initiate limited interventional trials. Because of the huge number of patients that receive anesthetics, and the public health and societal challenge of caring for the demented, it is imperative that we design our perioperative care in a way that avoids contributions to neurodegeneration. PUBLIC HEALTH RELEVANCE: Anesthetics have effects on the brain that outlast the period of anesthesia itself. The ability of volatile anesthetics to make proteins clump together (aggregation), produce pathology and learning and memory dysfunction resembling AD in mice, suggests the need for more rigorous evaluation of this issue, particularly in the elderly, as well as the need to investigate the safest anesthetic compounds.

描述（由申请人提供）：吸入麻醉药通过中间低聚物的稳定在体外增加了淀粉样蛋白β的聚集，这种物种被认为在阿尔茨海默氏病（AD）中引起神经认知功能障碍。其他人报告说，淀粉样蛋白β的产生也增加了。因此，吸入的麻醉药可能通过以毒性形式增加淀粉样蛋白β的脑浓度来导致认知减少。我们发现麻醉药增强了TG2576转基因小鼠（AD模型）的牙菌斑载荷，但没有产生增量的认知缺陷。我们怀疑这是由于新神经病理学产生认知能力下降的时间或不足的时间。现在，我们建议在具有3个转基因的最新动物模型中扩展这些研究，其中涉及AD发病机理的几个分子步骤。我们将通过将这些动物暴露于各个年龄段的五种不同麻醉药中来确定麻醉和AD之间的相互作用，以解决麻醉剂增强淀粉样蛋白和TAU组织病理学和认知能力下降的速率，以及特定脆弱性的窗口的存在。此外，小淀粉样蛋白β低聚物，高磷酸化的tau，caspase-3和突触标记物将在麻醉疫苗暴露后进行生化定量，以检验我们的机械假设。我们还将开始有限的介入试验。由于大量接受麻醉药的患者以及照顾痴呆症的公共卫生和社会挑战，因此我们必须以避免对神经变性的贡献的方式设计围手术期护理。公共卫生相关性：麻醉药对大脑的影响超过了麻醉本身的时期。挥发性麻醉药使蛋白质团结起来（聚集），产生病理学和学习以及类似于小鼠AD的记忆功能障碍的能力表明，需要对这个问题进行更严格的评估，尤其是在老年人中，以及需要研究最安全的麻醉化合物。