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 Aβ peptide. Excessive Cu and Fe ions binding to Aβ were suggested to have a deleterious effect on promoting both the aggregation of Aβ and the generation of reactive oxygen species (ROS). Other studies suggested that Aβ plays a protective role by acting as an antioxidant at nanomolar concentrations. The apparent confusion regarding the antioxidant and pro-oxidant properties of Aβ₄₀ encouraged us to explore the modulatory role of Aβ₄₀ at the molecular level under oxidative stress conditions. Here, we focused on Aβ₄₀ 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 Aβ₄₀. We found that Aβ₄₀, 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 μM. Aβ₄₀ proved to be 3.8-6.5 and 15-42 times more potent than the soluble Aβ₂₈ and the potent antioxidant Trolox, respectively, in the Cu(I)/Fe(II)-H₂O₂ systems. Time-dependent enhancement of ROS production by Aβ₄₀ occurs only at low concentrations of aggregated Aβ₄₀ and in the presence of Cu(II). On the basis of the extremely low IC₅₀ values of Aβ₄₀ and the extensive oxidative damage caused to Aβ₄₀ in Cu(I)/Fe (II)-H₂O₂ systems, we propose that radical scavenging is the major mechanism of antioxidant activity of Aβ₄₀ in addition to metal ion chelation. In summary, Aβ₄₀, 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 Aβ₄₀-Cu(I)/Fe(II) complex per se that is responsible for the oxidative damage in AD.