Soluble amyloid β1-28-copper(I)/copper(II)/iron(II) complexes are potent antioxidants in cell-free systems

Amyloid beta (A beta) is a central characteristic of Alzheimer's disease (AD). Currently, there is a long-standing dispute regarding the role of A beta-metal ion (Zn, Cu, and Fe) complexes in AD pathogenesis. Here, we aim to decipher the connection between oxidative damage implicated in AD and A beta-metal ion complexes. For this purpose we study, using ESR, the modulation of Cu/Fe-induced H2O2 decomposition by A beta(1-28) (A beta(28)), a soluble model of A beta(40/42). The addition of H2O2 to 0.6 nM-360 mu M A beta(28) solutions containing 100 mu M Cu(II)/Cu(I)/Fe(II) at pH 6.6 results in a concentration-dependent sigmoidal decay of [center dot OH] with IC50 values of 61, 59, and 84 mu M, respectively. Furthermore, A beta(28) reduces 90% of center dot OH production rate in the Cu(I)-H2O2 system in 5 min. Unlike soluble A beta(28), A beta(28)-Cu aggregates exhibit poor antioxidant activity. The mode of antioxidant activity of soluble A beta(28) is twofold. The primary (rapid) mechanism involves metal chelation, whereas the secondary (slow) mechanism involves (OH)-O-center dot scavenging and oxidation of Cu(Fe)-coordinating ligands. On the basis of our findings, we propose that soluble A beta may play a protective role in the early stages of AD, but not in healthy individuals, where A beta's concentration is nanomolar. Yet, when A beta-metal ion complexes undergo aggregation, they significantly lose their protective function and allow oxidative damage to occur.