Interactions of copper and copper chelate compounds with the amyloid beta peptide: An investigation into electrochemistry, reactive oxygen species and peptide aggregation

Abstract

Alzheimer's disease is a fatal neurological disorder affecting millions of people worldwide with an increasing patient population as average life expectancy increases. Accumulation of amyloid beta (Aβ) plaques is characteristic of the disease and has been the target of numerous failed clinical trials. In light of this, therapeutics that target mechanisms of neuronal death beyond Aβ aggregation are needed. One potential target is the formation of reactive oxygen species (ROS) that are created during an interaction between Aβ and copper ions. This work shows that ROS production can be slowed by disrupting the interaction between Aβ and copper using copper chelating compounds. We demonstrated that ROS are produced in the presence of Aβ and copper in solution by monitoring H₂O₂ production using a fluorescence-based assay, which increased when Cu²⁺ interacted with Aβ. In addition, we were able to show reduced ROS production, without exacerbating the aggregation of Aβ and in some cases alleviating it, by adding copper chelating ligands to the solution. Using cyclic voltammetry, we investigated how these different ligands influenced the electrochemical behavior of copper in solution revealing important insights into the mechanisms of ROS production and chemical interactions that result in decreased ROS rates.