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

Abstract

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.