Transfer of Copper from an Amyloid to a Natural Copper-Carrier Peptide with a Specific Mediating Ligand

The oxidative stress that arises from the catalytic reduction of dioxygen by Cu-II/I-loaded amyloids is the major pathway for neuron death that occurs in Alzheimer's disease. In this work, we show that bis-8(aminoquinoline) ligands, copper(II) specific chelators, are able to catalytically extract Cu-II from Cu-A beta(1-16) and then completely release Cu-I in the presence of glutathione to provide a Cu-I-glutathione complex, a biological intermediate that is able to deliver copper to apo forms of copper-protein complexes. These data demonstrate that bis-8(aminoquinolines) can perform the transfer of copper ions from the pathological Cu-amyloid complexes to regular copper-protein complexes. These copper-specific ligands assist GSH to recycle Cu-I in an AD brain and consequently slow down oxidative damage that is due to copper dysregulation in Alzheimer's disease. Under the same conditions, we have shown that the copper complex of PBT2, a mono(8-hydroxyquinoline) previously used as a drug candidate, does not efficiently release copper in the presence of GSH. In addition, we report that GSH itself was unable to fully abstract copper ions from Cu-beta-amyloid complexes.