Combining electron and nuclear magnetic resonance to track Alzheimer's amyloid-beta oligomer-to-fibril conversion

项目摘要/摘要 Aβ蛋白的聚集在阿尔茨海默病的发病机制中起着核心作用。β聚合 导致形成可溶低聚物和不溶纤维。而淀粉样纤维是主要成分 在阿尔茨海默病大脑中的实质斑块中，Aβ寡聚体被广泛认为比 毒性更强，更具病理性。有强有力的证据支持至少某些类型的β 齐聚物可以进行构象转换以形成纤维。然而，人们对这一现象是如何 低聚物可以重新排列它们的结构以形成纤维。在这个拟议的项目中，我们将结合使用 电子和核磁共振监测β-42齐聚物到纤维过程中的结构变化 转换。Aβ42齐聚物将在低浓度洗涤剂存在的情况下制备。这些 β42低聚物代表一种稳定的低聚物，只有在有脂类存在的情况下才能转化为纤维 水泡。低聚物转化为原纤维后，将进行EPR和核磁共振实验 不同的时间点。这项研究将提供关于齐聚物是否解离为单体的见解，这 然后成核形成原纤核，或低聚物不解离地过渡到原纤核的结构。我们 不仅描述了β聚集的机制，而且阐明了如何调节这一过程 作为治疗干预的一种方式。

Project Summary/Abstract Aggregation of Aβ protein plays a central role in the pathogenesis of Alzheimer's disease. Aβ aggregation leads to the formation of soluble oligomers and insoluble fibrils. While amyloid fibrils are the main component of parenchymal plaques in Alzheimer's disease brains, the Aβ oligomers have been widely regarded as more toxic and more pathologically relevant. There is strong evidence supporting that at least some types of Aβ oligomers can undergo a conformational conversion to form fibrils. It is yet poorly understood how the oligomers could re-arrange their structures to form fibrils. In this proposed project, we will use a combination of electron and nuclear magnetic resonance to monitor structural changes during Aβ42 oligomer-to-fibril conversion. The Aβ42 oligomers will be prepared in the presence of low concentrations of detergent. These Aβ42 oligomers represent a type of stable oligomers, which convert to fibrils only in the presence of lipid vesicles. The oligomer-to-fibril conversion will be followed by performing EPR and NMR experiments at different time points. This study will provide insights into whether oligomers dissociate to monomers, which then nucleate to form fibril nuclei, or oligomers transition to the structure of fibril nuclei without dissociation. We will not only delineate the mechanism of Aβ aggregation, but also shed light on how to modulate this process as a way of therapeutic intervention.