Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106-9510, USA.
Nat Chem. 2009 Jul;1(4):326-31. doi: 10.1038/nchem.247.
In recent years, small protein oligomers have been implicated in the aetiology of a number of important amyloid diseases, such as type 2 diabetes, Parkinson's disease and Alzheimer's disease. As a consequence, research efforts are being directed away from traditional targets, such as amyloid plaques, and towards characterization of early oligomer states. Here we present a new analysis method, ion mobility coupled with mass spectrometry, for this challenging problem, which allows determination of in vitro oligomer distributions and the qualitative structure of each of the aggregates. We applied these methods to a number of the amyloid-β protein isoforms of Aβ40 and Aβ42 and showed that their oligomer-size distributions are very different. Our results are consistent with previous observations that Aβ40 and Aβ42 self-assemble via different pathways and provide a candidate in the Aβ42 dodecamer for the primary toxic species in Alzheimer's disease.
近年来，小分子蛋白寡聚体与多种重要淀粉样疾病（如 2 型糖尿病、帕金森病和阿尔茨海默病）的病因有关。因此，研究工作正从传统的靶点（如淀粉样斑块）转向对早期寡聚状态的特征描述。在这里，我们提出了一种新的分析方法，即离子淌度与质谱联用，用于解决这一具有挑战性的问题，该方法可以确定体外寡聚体的分布以及每个聚集体的定性结构。我们将这些方法应用于 Aβ40 和 Aβ42 的一些淀粉样β蛋白异构体，并表明它们的寡聚体大小分布非常不同。我们的结果与之前的观察结果一致，即 Aβ40 和 Aβ42 通过不同的途径自组装，并为阿尔茨海默病中的主要毒性物质提供了 Aβ42 十二聚体的候选物。
