Metal-catalyzed oxidation of Aβ and the resulting reorganization of Cu binding sites promote ROS production†

In the context of Alzheimer’s disease (AD), the production of HO(•) by copper–amyloid beta (Aβ) in the presence of ascorbate is known to be deleterious for the Aβ peptide itself and also for the surrounding molecules, thus establishing a direct link between AD and oxidative stress. The metal-catalyzed oxidation (MCO) of Aβ primarily targets the residues involved in copper coordination during HO(•) production. In the present work, we demonstrate that the oxidative damage undergone by Aβ during MCO lead to a change in copper coordination, with enhanced catalytic properties that increases the rates of ascorbate consumption and HO(•) production, and the amount of HO(•) released by the system. This phenomenon is observed after the peptide has been sufficiently oxidized.