Soluble amyloid beta1-28-copper(I)/copper(II)/Iron(II) complexes are potent antioxidants in cell-free systems.
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.
Baruch-Suchodolsky
Rozena
R
Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel.
Fischer
Bilha
B
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D000975:Antioxidants / Q000737:chemistry* / Q000378:metabolism; D002474:Cell-Free System; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron