PDF(Pubmed)
Abstract：
Aβ oligomers are being investigated as cytotoxic agents in Alzheimer\'s disease (AD). Because of their transient nature and conformational heterogeneity, the relationship between the structure and activity of these oligomers is still poorly understood. Hence, methods for stabilizing Aβ oligomeric species relevant to AD are needed to uncover the structural determinants of their cytotoxicity. Here, we build on the observation that metal ions and metabolites have been shown to interact with Aβ, influencing its aggregation and stabilizing its oligomeric species. We thus developed a method that uses zinc ions, Zn(II), to stabilize oligomers produced by the 42-residue form of Aβ (Aβ42), which is dysregulated in AD. These Aβ42-Zn(II) oligomers are small in size, spanning the 10-30 nm range, stable at physiological temperature, and with a broad toxic profile in human neuroblastoma cells. These oligomers offer a tool to study the mechanisms of toxicity of Aβ oligomers in cellular and animal AD models.
摘要：
正在研究Aβ寡聚体作为阿尔茨海默病(AD)中的细胞毒性剂。由于它们的瞬时性质和构象异质性，这些寡聚体的结构和活性之间的关系仍然知之甚少。因此，需要稳定与AD相关的Aβ寡聚物种的方法来揭示其细胞毒性的结构决定因素。这里,我们基于金属离子和代谢物与Aβ相互作用的观察结果，影响其聚集并稳定其寡聚物种。因此，我们开发了一种使用锌离子的方法，Zn(II),稳定由42残基形式的Aβ（Aβ42）产生的低聚物，在AD中失调。这些Aβ42-Zn（II）低聚物尺寸小，跨越10-30nm的范围，在生理温度下稳定，在人类神经母细胞瘤细胞中具有广泛的毒性。这些寡聚体提供了研究细胞和动物AD模型中Aβ寡聚体的毒性机制的工具。
