Anesthetics and Alzheimer's Disease

麻醉药和阿尔茨海默病

• 批准号: 7844873
• 负责人: Roderic G Eckenhoff
• 金额: $ 31.85万
• 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/7844873
• 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）：吸入麻醉剂通过稳定中间低聚物来增加体外β淀粉样蛋白的聚集，这种物质被认为会导致阿尔茨海默病（AD）中的神经认知功能障碍。其他人报告说，β-淀粉样蛋白的产生也有所增加。因此，吸入麻醉剂可能会增加大脑中有毒形式的β淀粉样蛋白的浓度，从而导致认知能力下降。我们发现麻醉剂增加了 Tg2576 转基因小鼠（AD 模型）的斑块负荷，但没有增加认知缺陷。我们怀疑这是由于地板效应或新的神经病理学产生认知能力下降的时间不够。我们现在建议在具有 3 个转基因的更新的动物模型中扩展这些研究，涉及 AD 发病机制的几个分子步骤。我们将通过将这些动物在不同年龄暴露于五种不同的麻醉剂来确定麻醉剂与 AD 之间的相互作用，以解决麻醉剂会增强淀粉样蛋白和 tau 组织病理学发生率以及认知能力下降的假设，并且存在特定的脆弱性窗口。此外，小淀粉样β寡聚体、过度磷酸化的tau蛋白、caspase-3和突触标记物的水平将在麻醉剂暴露后进行生化定量，以测试我们的机制假设。我们还将启动有限的干预试验。由于接受麻醉的患者数量庞大，以及照顾痴呆症患者所面临的公共卫生和社会挑战，我们必须以避免导致神经退行性疾病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比麻醉本身的持续时间还要长。挥发性麻醉剂能够使蛋白质聚集在一起（聚集），在小鼠中产生类似于 AD 的病理学和学习记忆功能障碍，这表明需要对这个问题进行更严格的评估，特别是在老年人中，以及需要调查最安全的麻醉化合物。