Anesthetics and Alzheimer's Disease

描述(申请人提供)：吸入麻醉药通过稳定中间低聚物在体外增加淀粉样β蛋白的聚集，这是一种被认为导致阿尔茨海默病(AD)神经认知功能障碍的物种。其他人报告说，淀粉样β蛋白的产生也增加了。因此，吸入麻醉剂可能通过以有毒形式增加大脑中淀粉样β蛋白的浓度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，但没有产生递增的认知缺陷。我们怀疑这要么是因为地板效应，要么是因为新的神经病理学没有足够的时间来产生认知能力下降。我们现在建议在一个较新的动物模型中扩展这些研究，其中有3个转基因，涉及AD发病机制中的几个分子步骤。我们将通过在不同年龄将这些动物暴露于五种不同的麻醉剂来确定麻醉剂和AD之间的相互作用，以解决这样的假设，即麻醉剂增加了淀粉样蛋白和tau蛋白的组织病理学和认知功能下降的比率，并且存在一个特定的易损性窗口。此外，麻醉后小淀粉样β寡聚体、过度磷酸化的tau、caspase-3和突触标志物的水平将被生化定量，以检验我们的机制假说。我们还将启动有限的干预性试验。由于接受麻醉药的患者数量巨大，以及照顾痴呆者的公共卫生和社会挑战，我们必须设计一种避免导致神经退化的围术期护理。公共卫生相关性：麻醉剂对大脑的影响持续时间超过麻醉期本身。挥发性麻醉剂能够使蛋白质聚集(聚集)，在小鼠身上产生类似AD的病理和学习记忆功能障碍，这表明需要对这一问题进行更严格的评估，特别是在老年人中，以及研究最安全的麻醉剂化合物的必要性。

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.