Oxidative Activity of Copper Ions in Ternary Systems With N-Truncated Amyloid Beta Peptides and Low Molecular Weight Substances

Abstract

Oxidative stress is one of the most characteristic features of Alzheimer's disease. Previous studies revealed that copper complexes of amyloid beta (Aβ) peptides, mainly the Aβ_1-x form, could effectively catalyze the production of reactive oxygen species (ROS), causing the oxidation of physiological compounds. The Cu(II) binding to N-truncated Aβ forms containing His-2 and His-3 motifs produced less oxidative damage by arresting the Cu(II) ions in highly stable Cu(II)/Aβ complexes. This could be reversed, however, by interactions with low molecular weight (LMW) substances. In this work, we investigated the influence of biologically relevant LMW: His-1 dipeptide His-Leu, histidine, imidazole, and neurotransmitters histamine, glycine, and glutamate on the ROS-related ascorbate oxidation by Cu(II) complexes of Aβ peptides comprising the His-2 and His-3 motifs, namely Aβ_4-9, Aβ_5-9, and Aβ_12-16. These peptides are putative products of Aβ hydrolysis by protease neprilysin. A significantly higher efficiency in the ascorbate oxidation was observed for the ternary Cu(II)/Aβ/LMW systems with His-Leu and histidine compared to the binary Cu(II)/Aβ complexes. The effect was more pronounced for the systems with Aβ_4-9 (the His-3 motif only) than those with Aβ_5-9 and Aβ_12-16 (containing the His-2 motif), which is likely connected with a faster Cu(II) trapping by the His-2 peptides compared to the His-3 peptides. The obtained results raise further questions regarding the copper redox activity in Alzheimer's disease.