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.