Aβ40, either Soluble or Aggregated, Is a Remarkably Potent Antioxidant in Cell-Free Oxidative Systems

The brains of individuals diagnosed with Alzheimer's disease (AD) are characterized by amyloid plaques, of which the major component is A beta peptide. Excessive Cu and Fe ions binding to A beta were suggested to have a deleterious effect on promoting both the aggregation of A beta and the generation of reactive oxygen species (ROS). Other studies suggested that A beta plays a protective role by acting as an antioxidant at nanomolar concentrations. The apparent confusion regarding the antioxidant and pro-oxidant properties of A beta(40) encouraged us to explore the modulatory role of A beta(40) at the molecular level under oxidative stress conditions. Here, we focused on A beta(40) in the simplest oxidative system, namely, Cu(I)/Cu(II)/Fe(II)-H2O2. Using ESR, we monitored the production of OH radicals in the above-mentioned systems in the presence of A beta(40). We found that A beta(40), either in its soluble or in its aggregated form, functioned as a remarkably potent antioxidant in Cu(I)/Fe(II)-catalyzed radical-producing systems and slightly less potently in the presence of Cu(II) with IC50 values of 13-62 mu M. A beta(40) proved to be 3.8-6.5 and 15-42 times more potent than the soluble A beta(28) and the potent antioxidant Trolox, respectively, in the Cu(I)/Fe(II)-H2O2 systems. Time-dependent enhancement of ROS production by A beta(40) occurs only at low concentrations of aggregated A beta(40) and in the presence of Cu(II). On the basis of the extremely low IC50 values of A beta(40) and the extensive oxidative damage caused to A beta(40) in Cu(I)/Fe (II)-H2O2 systems, we propose that radical scavenging is the major mechanism of antioxidant activity of A beta(40) in addition to metal ion chelation. In summary, A beta(40), either soluble or aggregated, at either nanomolar or micromolar concentrations is a highly potent antioxidant in cell-free oxidative systems, acting mainly as a radical scavenger. Therefore, we propose that it is not the A beta(40)-Cu(I)/Fe(II) complex per se that is responsible for the oxidative damage in AD.