Insights into the Mechanisms of Amyloid Formation of Zn^II-Ab11-28: pH-Dependent Zinc Coordination and Overall Charge as Key Parameters for Kinetics and the Structure of Zn^II-Ab11-28 Aggregates

Self-assembly of amyloidogenic peptides and their metal complexes are of multiple interest including their association with several neurological diseases. Therefore, a better understanding of the role of metal ions in the aggregation process is of broad interest. We report pH-dependent structural and aggregation studies on Zn^II binding to the amyloidogenic peptide Ab11-28. The results suggest that coordination of the N-terminal amine to Zn^II is responsible for the inhibition of amyloid formation and the overall charge for amorphous aggregates

Copper Coordination to Native N‑Terminally Modified versus Full-Length Amyloid-β: Second-Sphere Effects Determine the Species Present at Physiological pH

Alzheimer’s disease is characterized by senile plaques in which metallic ions (copper, zinc, and iron) are colocalized with amyloid-β peptides of different sequences in aggregated forms. In addition to the full-length peptides (Aβ1-40/42), N-terminally truncated Aβ3-40/42 forms and their pyroglutamate counterparts, Aβp3-40/42, have been proposed to play key features in the aggregation process, leading to the senile plaques. Furthermore, they have been shown to be more toxic than the full-length Aβ, which made them central targets for therapeutic approaches. In order to better disentangle the possible role of metallic ions in the aggregation process, copper­(II) coordination to the full-length amyloid peptides has been extensively studied in the last years. However, regarding the N-terminally modified forms at position 3, very little is known. Therefore, copper­(I) and copper­(II) coordination to those peptides have been investigated in the present report using a variety of complementary techniques and as a function of pH. Copper­(I) coordination is not affected by the N-terminal modifications. In contrast, copper­(II) coordination is different from that previously reported for the full-length peptide. In the case of the pyroglutamate form, this is due to preclusion of N-terminal amine binding. In the case of the N-terminally truncated form, alteration in copper­(II) coordination is caused by second-sphere effects that impact the first binding shell and the pH-dependent repartition of the various [Cu­(peptide)] complexes. Such second-sphere effects are anticipated to apply to a variety of metal ions and peptides, and their importance on changing the first binding shell has not been fully recognized yet