Anesthetics and Alzheimer's Disease

描述（由申请人提供）：吸入麻醉剂通过稳定中间低聚物在体外增加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）的神经认知功能障碍。其他人也报道了β淀粉样蛋白的产生也增加了。因此，吸入麻醉剂可能通过增加大脑中有毒形式的β淀粉样蛋白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（一种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没有足够的时间让新的神经病理学产生认知能力下降。我们现在建议在最近的动物模型中扩展这些研究，包括3个转基因，涉及阿尔茨海默病发病的几个分子步骤。我们将通过将这些动物暴露在不同年龄的五种不同的麻醉剂中来确定麻醉剂与AD之间的相互作用，以解决麻醉剂提高淀粉样蛋白和tau组织病理学和认知能力下降的速度的假设，以及存在特定的易感性窗口。此外，小淀粉样蛋白低聚物、过度磷酸化的tau蛋白、caspase-3和突触标记物的水平将在麻醉暴露后进行生化定量，以检验我们的机制假设。我们还将启动有限的干预性试验。由于大量患者接受麻醉，以及照顾痴呆患者的公共卫生和社会挑战，我们必须设计围手术期护理，以避免对神经变性的贡献。公共卫生相关性：麻醉剂对大脑的影响持续时间超过麻醉本身。挥发性麻醉剂能够使蛋白质聚集在一起（聚集），在小鼠中产生类似阿尔茨海默病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，以及需要研究最安全的麻醉化合物。

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.