Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation-inert complex.

A detailed understanding of the molecular pathways for amyloid-beta (Abeta) 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 Abeta peptide and efficiently modulates Abeta 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 Abeta monomers to its macroscopic impact on the peptide self-assembly observed in bulk experiments. We found that sub-stoichiometric concentrations of the investigated metal ions bind specifically to the N-terminal region of Abeta, forming a dynamic, partially compact complex. The metal ion bound state appears to be incapable of aggregation, effectively reducing the available monomeric Abeta pool for incorporation into fibrils. This is especially reflected in a decreased fibril-end elongation rate. However, since the bound state is significantly less stable than the amyloid state, Abeta peptides are only transiently redirected from fibril formation and eventually almost all Abeta monomers are integrated into fibrils. Taken together, these findings unravel the mechanistic consequences of delaying Abeta aggregation via weak metal ion binding, quantitatively linking the contributions of specific interactions of metal ions with monomeric Abeta to their effects on bulk aggregation.