title: Transfer of Copper from an Amyloid to a Natural Copper-Carrier Peptide with a Specific Mediating Ligand.
abstract: 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-Aβ1-16 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-β-amyloid complexes.
authors.affiliation: Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, BP 44099, 31077 Toulouse cedex 4 (France).
authors.forename: Michel
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, BP 44099, 31077 Toulouse cedex 4 (France).
authors.forename: Christian
authors.initials: C
authors.lastname: Bijani
authors.affiliation: Université de Toulouse, Service Commun de Spectrométrie de Masse, 31077 Toulouse cedex 4 (France).
authors.forename: Nathalie
authors.initials: N
authors.lastname: Martins
authors.affiliation: Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, BP 44099, 31077 Toulouse cedex 4 (France). bernard.meunier@lcc-toulouse.fr.|Guangdong University of Technology, Department of Chemical Engineering, no. 100 Waihuan Xi road, Education Mega Center, Panyu District, Guangzhou (P. R. China). bernard.meunier@lcc-toulouse.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Meunier
authors.affiliation: Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, BP 44099, 31077 Toulouse cedex 4 (France). anne.robert@lcc-toulouse.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Robert
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000595:Amino Acid Sequence; D000634:Aminoquinolines / Q000737:chemistry*; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry*; D008024:Ligands; D010084:Oxidation-Reduction; D018384:Oxidative Stress
chemical_list: D000634:Aminoquinolines; D000682:Amyloid; D016229:Amyloid beta-Peptides; D056831:Coordination Complexes; D008024:Ligands; C000608029:bis-8(aminoquinoline); D003300:Copper; D006861:Hydrogen Peroxide; D005978:Glutathione
keywords: alzheimer’s disease; aminoquinoline; chelates; copper; medicinal chemistry