Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease β‐amyloid

Abstract

SPECIFIC AIMSThe β-amyloid peptide (Aβ), which plays a central role in the progression of Alzheimer’s disease, is neurotoxic. This toxicity has been linked to generation of H2O2. Aβ coordinates redox active transition metals, copper, and iron to catalytically generate reactive oxygen species. The chemical mechanism underlying this process is not well defined. We have examined this mechanism to gain a better understanding of factors regulating Aβ neurotoxicity.PRINCIPAL FINDINGS1. Tyrosine10 (Y10) is a pivotal residue to drive catalytic production of H2O2 by Aβ/CuWhen Aβ binds Cu it activates oxygen and in the presence of a reducing substrate (ascorbic acid is used in this study) catalyzes reduction of oxygen to H2O2 by promoting transfer of two electrons and two protons from the substrate to O2. To identify molecular events underlying Aβ/Cu2+-catalyzed production of H2O2, we performed density functional theory (DFT) calculations.DFT calculations suggest that Cu2+ is reduced to Cu+ via proton-coupled elect...