Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease.
Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease.
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近年来，小蛋白寡聚体与许多重要的淀粉样蛋白疾病的病因有关，例如2型糖尿病、帕金森病和阿尔茨海默病。因此，研究工作正在从淀粉样斑块等传统目标转向早期寡聚物状态的表征。在这里，我们针对这一具有挑战性的问题提出了一种新的分析方法，即离子淌度与质谱联用，可以确定体外低聚物分布和每种聚集体的定性结构。我们将这些方法应用于 Aβ40 和 Aβ42 的多种淀粉样蛋白-β 蛋白亚型，结果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 Aβ42 十二聚体中的候选者提供了阿尔茨海默氏病的主要有毒物质。
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.