Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
Department of Biochemistry & Structural Biology, Center for Molecular Protein Science, Lund University, PO box 124, 221 00 Lund, Sweden.
ACS Chem Neurosci. 2024 Mar 20;15(6):1125-1134. doi: 10.1021/acschemneuro.3c00718. Epub 2024 Feb 28.
Oligomeric assemblies of the amyloid β peptide (Aβ) have been investigated for over two decades as possible neurotoxic agents in Alzheimer's disease. However, due to their heterogeneous and transient nature, it is not yet fully established which of the structural features of these oligomers may generate cellular damage. Here, we study distinct oligomer species formed by Aβ40 (the 40-residue form of Aβ) in the presence of four different metal ions (Al, Cu, Fe, and Zn) and show that they differ in their structure and toxicity in human neuroblastoma cells. We then describe a correlation between the size of the oligomers and their neurotoxic activity, which provides a type of structure-toxicity relationship for these Aβ40 oligomer species. These results provide insight into the possible role of metal ions in Alzheimer's disease by the stabilization of Aβ oligomers.
寡聚体的淀粉样β肽（Aβ）已被研究了二十多年，作为阿尔茨海默病中可能的神经毒性剂。然而，由于其异构和瞬态的性质，目前还不完全确定这些寡聚物的结构特征中的哪一个可能产生细胞损伤。在这里，我们研究了在存在四种不同金属离子（Al、Cu、Fe 和 Zn）的情况下由 Aβ40（Aβ 的 40 个残基形式）形成的不同寡聚物物种，并表明它们在结构和对人神经母细胞瘤细胞的毒性上存在差异。然后，我们描述了寡聚物的大小与其神经毒性活性之间的相关性，这为这些 Aβ40 寡聚物物种提供了一种结构-毒性关系。这些结果通过稳定 Aβ 寡聚物，为金属离子在阿尔茨海默病中的可能作用提供了一些见解。
