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

Dalton Trans. 2024 Sep 18;53(36):15359-15371. doi: 10.1039/d4dt01354a.

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, Aβ4-9, Aβ5-9, and Aβ12-16, 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.

MeSH terms

  • Amyloid beta-Peptides* / chemistry
  • Amyloid beta-Peptides* / metabolism
  • Coordination Complexes* / chemical synthesis
  • Coordination Complexes* / chemistry
  • Copper* / chemistry
  • Electrochemical Techniques*
  • Histamine* / chemistry
  • Histidine* / chemistry
  • Imidazoles* / chemistry
  • Oxidation-Reduction

Substances

  • Copper
  • Amyloid beta-Peptides
  • Histidine
  • Coordination Complexes
  • Imidazoles
  • Histamine
  • imidazole