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

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 Cu2+ -catalyzed reactive oxygen species (ROS) generation by using oligomers prepared in phosphate-buffered saline (AßO-PBS ) and in cell culture medium (AßO-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 AßO-PBS oligomers have a spherical morphology and are smaller than the AßO-CCM . The AßO-PBS behaved as pro-oxidants; in contrast, AßO-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 Aß 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 Cu2+ in 21 ratio and abolished ROS production in all Aß species. It also distinctly modified the folding landscape of Aß species into new or altered morphologies.