Anesthetics and Alzheimer's Disease

描述（由申请方提供）：吸入麻醉剂通过稳定中间低聚物（一种被认为会导致阿尔茨海默病（AD）神经认知功能障碍的物质），在体外增加β淀粉样蛋白的聚集。其他人报道淀粉样蛋白β的产生也增加。因此，吸入麻醉剂可能通过增加毒性形式的β淀粉样蛋白的脑浓度而导致认知能力下降。我们已经发现，麻醉剂增加Tg 2576转基因小鼠（AD模型）的斑块负荷，但不产生增量认知缺陷。我们怀疑这是由于地板效应或新的神经病理学没有足够的时间产生认知能力下降。我们现在建议扩大这些研究在最近的动物模型与3个转基因，涉及几个分子步骤，在AD发病机制。我们将通过将这些动物在不同年龄段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存在特定脆弱性窗口的假设。此外，将在麻醉暴露后对小淀粉样蛋白β寡聚体、过度磷酸化tau、半胱天冬酶-3和突触标志物的水平进行生化定量，以检验我们的机制假设。我们还将启动有限的干预性试验。由于接受麻醉的患者数量巨大，以及照顾痴呆症患者的公共卫生和社会挑战，我们必须以避免神经退行性变的方式设计围手术期护理。公共卫生相关性：麻醉剂对大脑的影响超过了麻醉本身的时间。挥发性麻醉剂能够使蛋白质聚集在一起（聚集），产生类似于小鼠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，以及需要研究最安全的麻醉剂化合物。

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.