Impact of N-Truncated Aβ Peptides on Cu- and Cu(Aβ)-Generated ROS: CuI Matters!

Abstract

In vitro Cu(Aβ_1-x )-induced ROS production has been extensively studied. Conversely, the ability of N-truncated isoforms of Aβ to alter the Cu-induced ROS production has been overlooked, even though they are main constituents of amyloid plaques found in the human brain. N-Truncated peptides at the positions 4 and 11 (Aβ_4-x and Aβ_11-x ) contain an amino-terminal copper and nickel (ATCUN) binding motif (H₂ N-Xxx-Zzz-His) that confer them different coordination sites and higher affinities for Cu^II compared to the Aβ_1-x peptide. It has further been proposed that the role of Aβ_4-x peptide is to quench Cu^II toxicity in the brain. However, the role of Cu^I coordination has not been investigated to date. In contrast to Cu^II , Cu^I coordination is expected to be the same for N-truncated and N-intact peptides. Herein, we report in-depth characterizations and ROS production studies of Cu (Cu^I and Cu^II ) complexes of the Aβ_4-16 and Aβ_11-16 N-truncated peptides. Our findings show that the N-truncated peptides do produce ROS when Cu^I is present in the medium, albeit to a lesser extent than the unmodified counterpart. In addition, when used as competitor ligands (i.e., in the presence of Aβ_1-16 ), the N-truncated peptides are not able to fully preclude Cu(Aβ_1-16 )-induced ROS production.

Keywords: amyloid beta-peptides; bioinorganic chemistry; chelates; copper; reactive oxygen species.