The effect of histidine, histamine, and imidazole on electrochemical properties of Cu(ii) complexes of Aβ peptides containing His-2 and His-3 motifs

Abstract

The N-truncation of amyloid beta (Aβ) peptides could lead to peptide sequences with the histidine residue at the second and third positions, creating His-2 and His-3 motifs, known as high-affinity Cu(II) binding sites. In such complexes, the Cu(II) ion is arrested in a rigid structure of a square-planar arrangement of nitrogen donors, which highly limits its susceptibility to Cu(II) reduction. Cu(II) reduction fuels the Cu(II)/Cu(I) redox cycle, which is engaged in the production of reactive oxygen species (ROS). Employing electrochemical techniques, cyclic voltammetry (CV) and differential pulse voltammetry (DPV), together with UV–vis spectroscopy, we showed that low-molecular-weight (LMW) substances, such as imidazole, histamine, and histidine, could enhance the redox activity of Cu(II) complexes of three models of N-truncated Aβ peptides, Aβ_4–9, Aβ_5–9, and Aβ_12–16, identifying three main mechanisms. LMW compounds could effectively compete with Aβ peptides for Cu(II) ions, forming Cu(II)/LMW species, which are more prone to Cu(II) reduction. LMW substances could also shift the equilibrium between the Cu(II)/Aβ species towards the species with higher susceptibility to Cu(II) reduction. Finally, the presence of LMW molecules could promote Cu(I) reoxidation in ternary Cu(II)/Aβ/LMW systems. The obtained results raise further questions regarding the Cu(II) redox activity in Alzheimer's disease.