Interaction of amyloid beta and inhaled anesthetics

描述(由申请人提供)： 在麻醉和手术后，认知能力下降，在老年人和那些先前存在神经退行性疾病的人中最为明显。认知能力的丧失似乎与手术类型无关，这表明麻醉可能起到了作用。我们对吸入麻醉剂-蛋白质相互作用的研究表明，这些小的疏水配体可以有效地促进蛋白质齐聚，特别是在小的、不稳定的多肽中。我们的分子假说是，吸入麻醉剂通过优先结合寡聚体中的许多分子间空腔来改变寡聚平衡。由于这种寡聚被认为是阿尔茨海默氏症、帕金森氏症和亨廷顿病等神经退行性疾病的近端致病事件，因此吸入麻醉剂将被预测为加速这些疾病。我们建议用体外分子和细胞培养系统来检验这一假设。具体目标1将通过光散射、电子显微镜、结合分析、尺寸排斥层析和超速离心法检测七种全身麻醉药对不同淀粉样β多肽齐聚的影响来确定这一假说的可行性。目标1的主要目标是建立齐聚能力的等级顺序。特定的AIM 2将测试这些体外观察是否在细胞培养中转化为增强的细胞毒性或淀粉样β蛋白的凋亡，使用等级顺序建立与AIM 1机制的联系。这些研究将为将这一假说扩展到动物模型，并最终扩展到麻醉剂和神经退行性变之间相互作用的临床研究提供可行性。

DESCRIPTION (provided by applicant): Cognitive decline occurs after anesthesia and surgery, and is most pronounced in the elderly and perhaps in those with pre-existing neurodegenerative disorders. Loss of cognition appears to be unrelated to type of surgery, suggesting that anesthesia may contribute. Our research into inhaled anesthetic-protein interactions shows that these small hydrophobic ligands can potently promote protein oligomerization especially in small, unstable peptides. Our molecular hypothesis for this is that inhaled anesthetics shift oligomerization equilibria through preferential binding to numerous intermolecular cavities in the oligomer. Since such oligomerization is thought to be a proximal pathogenic event in the neurodegenerative disorders like Alzheimer's, Parkinson's and Huntington's diseases, inhaled anesthetics would be predicted to accelerate these disorders. We propose to test this hypothesis with in vitro molecular, and cell culture systems. Specific aim 1 will establish the feasibility of this hypothesis by examining the effect of seven general anesthetics on oligomerization of different amyloid beta peptides using light scattering, electron microscopy, binding assays, size exclusion chromatography and ultracentrifugation. A primary goal of aim 1 is to establish a rank-order of oligomerization potency. Specific aim 2 will test whether these in vitro observations translate into enhanced cytotoxicity or apoptosis of amyloid beta in cell culture, using the rank order to establish a link to the aim 1 mechanism. These studies will provide the feasibility to extend this hypothesis to animal models and ultimately to clinical studies of the interaction between anesthetics and neurodegeneration.