Soluble amyloid β_1-28-copper(I)/copper(II)/iron(II) complexes are potent antioxidants in cell-free systems

Amyloid β (Aβ) is a central characteristic of Alzheimer's disease (AD). Currently, there is a long-standing dispute regarding the role of Aβ-metal ion (Zn, Cu, and Fe) complexes in AD pathogenesis. Here, we aim to decipher the connection between oxidative damage implicated in AD and Aβ-metal ion complexes. For this purpose we study, using ESR, the modulation of Cu/Fe-induced H₂O₂ decomposition by Aβ_1-28 (Aβ₂₈), a soluble model of Aβ_40/42. The addition of H₂O₂ to 0.6 nM-360 μM Aβ₂₈ solutions containing 100 μM Cu(II)/Cu(I)/Fe(II) at pH 6.6 results in a concentration-dependent sigmoidal decay of [·OH] with IC₅₀ values of 61, 59, and 84 μM, respectively. Furthermore, Aβ₂₈ reduces 90% of ·OH production rate in the Cu(I)-H₂O₂ system in 5 min. Unlike soluble Aβ₂₈, Aβ₂₈-Cu aggregates exhibit poor antioxidant activity. The mode of antioxidant activity of soluble Aβ₂₈ 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 Aβ may play a protective role in the early stages of AD, but not in healthy individuals, where Aβ' s concentration is nanomolar. Yet, when Aβ-metal ion complexes undergo aggregation, they significantly lose their protective function and allow oxidative damage to occur.