A Unified View of Assessing the Pro‐oxidant versus Antioxidant Nature of Amyloid Beta Conformers

Abstract

Abstract Transition‐metal‐catalyzed oxidative stress is a widespread concern in the pathogenesis of Alzheimer's disease. However, the exact role of amyloid beta oligomers towards oxidative stress is widely debated. Assessing the oxidative nature of the oligomers in vitro is complicated by the different experimental conditions under which they are prepared. We have investigated Cu 2+ ‐catalyzed reactive oxygen species (ROS) generation by using oligomers prepared in phosphate‐buffered saline (Aβ O‐PBS ) and in cell culture medium (Aβ O‐CCM ), and compared their activities with respect to the monomers and fibrils prepared at neutral and acidic pH. Although both are deca‐ to dodecamers, the Aβ O‐PBS oligomers have a spherical morphology and are smaller than the Aβ O‐CCM . The Aβ O‐PBS behaved as pro‐oxidants; in contrast, Aβ O‐CCM quench OH . generation attributed to CCM itself. Although the pro‐oxidant oligomers showed oxidation, they also partially protect themselves from radical damage and maintain their overall spherical arrangement. The monomers and fibrils manifested antioxidant properties: radical scavenging as opposed to redox silencing. A dual role of Aβ species depending on the stage of the disease is proposed. In the earlier stages, the monomers can act as antioxidants, whereas at the later stages, the oligomers take on a pro‐oxidant role. Kaempferol, a natural flavonoid, bound Cu 2+ in 2:1 ratio and abolished ROS production in all Aβ species. It also distinctly modified the folding landscape of Aβ species into new or altered morphologies.