The brains of individuals diagnosed with Alzheimer's disease (AD) are characterized by amyloid plaques, of which the major component is Abeta peptide. Excessive Cu and Fe ions binding to Abeta were suggested to have a deleterious effect on promoting both the aggregation of Abeta and the generation of reactive oxygen species (ROS). Other studies suggested that Abeta plays a protective role by acting as an antioxidant at nanomolar concentrations. The apparent confusion regarding the antioxidant and pro-oxidant properties of Abeta(40) encouraged us to explore the modulatory role of Abeta(40) at the molecular level under oxidative stress conditions. Here, we focused on Abeta(40) in the simplest oxidative system, namely, Cu(I)/Cu(II)/Fe(II)-H(2)O(2). Using ESR, we monitored the production of OH radicals in the above-mentioned systems in the presence of Abeta(40). We found that Abeta(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 IC(50) values of 13-62 muM. Abeta(40) proved to be 3.8-6.5 and 15-42 times more potent than the soluble Abeta(28) and the potent antioxidant Trolox, respectively, in the Cu(I)/Fe(II)-H(2)O(2) systems. Time-dependent enhancement of ROS production by Abeta(40) occurs only at low concentrations of aggregated Abeta(40) and in the presence of Cu(II). On the basis of the extremely low IC(50) values of Abeta(40) and the extensive oxidative damage caused to Abeta(40) in Cu(I)/Fe(II)-H(2)O(2) systems, we propose that radical scavenging is the major mechanism of antioxidant activity of Abeta(40) in addition to metal ion chelation. In summary, Abeta(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 Abeta(40)-Cu(I)/Fe(II) complex per se that is responsible for the oxidative damage in AD.

Amyloid beta (Abeta) is a central characteristic of Alzheimer's disease (AD). Currently, there is a long-standing dispute regarding the role of Abeta-metal ion (Zn, Cu, and Fe) complexes in AD pathogenesis. Here, we aim to decipher the connection between oxidative damage implicated in AD and Abeta-metal ion complexes. For this purpose we study, using ESR, the modulation of Cu/Fe-induced H 2O 2 decomposition by Abeta 1-28 (Abeta 28), a soluble model of Abeta 40/42. The addition of H 2O 2 to 0.6 nM-360 microM Abeta 28 solutions containing 100 microM Cu(II)/Cu(I)/Fe(II) at pH 6.6 results in a concentration-dependent sigmoidal decay of [*OH] with IC 50 values of 61, 59, and 84 microM, respectively. Furthermore, Abeta 28 reduces 90% of *OH production rate in the Cu(I)-H 2O 2 system in 5 min. Unlike soluble Abeta 28, Abeta 28-Cu aggregates exhibit poor antioxidant activity. The mode of antioxidant activity of soluble Abeta 28 is twofold. The primary (rapid) mechanism involves metal chelation, whereas the secondary (slow) mechanism involves (*)OH scavenging and oxidation of Cu(Fe)-coordinating ligands. On the basis of our findings, we propose that soluble Abeta may play a protective role in the early stages of AD, but not in healthy individuals, where Abeta's concentration is nanomolar. Yet, when Abeta-metal ion complexes undergo aggregation, they significantly lose their protective function and allow oxidative damage to occur.

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