Centre for Misfolding Diseases, Department of Chemistry , University of Cambridge , Cambridge CB2 1EW , UK.
Cavendish Laboratory, Department of Physics , University of Cambridge , Cambridge CB3 0HE , UK.
ACS Chem Neurosci. 2018 Dec 19;9(12):2959-2971. doi: 10.1021/acschemneuro.8b00141. Epub 2018 Aug 10.
Small oligomers formed during the aggregation of certain peptides and proteins are highly cytotoxic in numerous neurodegenerative disorders. Because of their transient nature and conformational heterogeneity, however, the structural and biological features of these oligomers are still poorly understood. Here, we describe a method of generating stable oligomers formed by the Alzheimer's Aβ peptide by carrying out an aggregation reaction in the presence of zinc ions. The resulting oligomers are amenable to detailed biophysical and biological characterization, which reveals a homogeneous population with small size, high cross-β sheet structure content, and extended hydrophobic surface patches. We also show that these oligomers decrease the viability of neuroblastoma cells and impair the motility of C. elegans. The availability of these oligomers offers novel opportunities for studying the mechanisms of Aβ toxicity in vitro and in cellular and animal models of Alzheimer's disease.
在某些肽和蛋白质的聚集过程中形成的小寡聚物在许多神经退行性疾病中具有高度细胞毒性。然而，由于它们的瞬态性质和构象异质性，这些寡聚物的结构和生物学特征仍然知之甚少。在这里，我们描述了一种通过在锌离子存在下进行聚集反应来生成由阿尔茨海默病 Aβ 肽形成的稳定寡聚物的方法。所得寡聚物适合进行详细的生物物理和生物学特性分析，结果表明其为具有小尺寸、高交叉-β 片层结构含量和扩展疏水面积的均一群体。我们还表明，这些寡聚物降低了神经母细胞瘤细胞的活力并损害了秀丽隐杆线虫的运动能力。这些寡聚物的可用性为在体外以及在阿尔茨海默病的细胞和动物模型中研究 Aβ 毒性的机制提供了新的机会。
