A detailed understanding of the molecular pathways for amyloid-β (Aβ) peptide aggregation from monomers into amyloid fibrils, a hallmark of Alzheimer's disease, is crucial for the development of diagnostic and therapeutic strategies. We investigate the molecular details of peptide fibrillization in vitro by perturbing this process through addition of differently charged metal ions. Here, we used a monovalent probe, the silver ion, that, similarly to divalent metal ions, binds to monomeric Aβ peptide and efficiently modulates Aβ fibrillization. On the basis of our findings, combined with our previous results on divalent zinc ions, we propose a model that links the microscopic metal-ion binding to Aβ monomers to its macroscopic impact on the peptide self-assembly observed in bulk experiments. We found that substoichiometric concentrations of the investigated metal ions bind specifically to the N-terminal region of Aβ, forming a dynamic, partially compact complex. The metal-ion bound state appears to be incapable of aggregation, effectively reducing the available monomeric Aβ pool for incorporation into fibrils. This is especially reflected in a decreased fibril-end elongation rate. However, because the bound state is significantly less stable than the amyloid state, Aβ peptides are only transiently redirected from fibril formation, and eventually almost all Aβ monomers are integrated into fibrils. Taken together, these findings unravel the mechanistic consequences of delaying Aβ aggregation via weak metal-ion binding, quantitatively linking the contributions of specific interactions of metal ions with monomeric Aβ to their effects on bulk aggregation.

中文翻译：

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金属离子配位通过形成聚集惰性复合物来延迟淀粉样蛋白-β肽的自组装。


详细了解淀粉样蛋白-β (Aβ) 肽从单体聚集成淀粉样原纤维（阿尔茨海默病的标志）的分子途径对于诊断和治疗策略的制定至关重要。我们通过添加不同电荷的金属离子扰乱这一过程来研究体外肽纤维化的分子细节。在这里，我们使用了单价探针，即银离子，与二价金属离子类似，它与单体 Aβ 肽结合并有效调节 Aβ 纤维化。根据我们的发现，结合我们之前对二价锌离子的研究结果，我们提出了一个模型，将与 Aβ 单体结合的微观金属离子与其在批量实验中观察到的肽自组装的宏观影响联系起来。我们发现，所研究的金属离子的亚化学计量浓度与 Aβ 的 N 末端区域特异性结合，形成动态的、部分致密的复合物。金属离子结合态似乎无法聚集，有效减少了可用于掺入原纤维的单体 Aβ 库。这尤其反映在原纤维末端伸长率的降低上。然而，由于结合状态明显不如淀粉样蛋白状态稳定，Aβ肽仅从原纤维形成中短暂地重定向，最终几乎所有Aβ单体都整合到原纤维中。总而言之，这些发现揭示了通过弱金属离子结合延迟 Aβ 聚集的机制后果，定量地将金属离子与单体 Aβ 的特定相互作用的贡献与其对整体聚集的影响联系起来。