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

ABSTRACT

In vitro Cu(Aß1-x )-induced ROS production has been extensively studied. Conversely, the ability of N-truncated isoforms of Aß 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 (Aß4-x and Aß11-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 CuII compared to the Aß1-x peptide. It has further been proposed that the role of Aß4-x peptide is to quench CuII toxicity in the brain. However, the role of CuI coordination has not been investigated to date. In contrast to CuII , CuI 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 (CuI and CuII ) complexes of the Aß4-16 and Aß11-16 N-truncated peptides. Our findings show that the N-truncated peptides do produce ROS when CuI 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 Aß1-16 ), the N-truncated peptides are not able to fully preclude Cu(Aß1-16 )-induced ROS production.