title: β-amyloid fibrils in Alzheimer disease are not inert when bound to copper ions but can degrade hydrogen peroxide and generate reactive oxygen species.
abstract: According to the "amyloid cascade" hypothesis of Alzheimer disease, the formation of Aβ fibrils and senile plaques in the brain initiates a cascade of events leading to the formation of neurofibrillary tangles, neurodegeneration, and the symptom of dementia. Recently, however, emphasis has shifted away from amyloid fibrils as the predominant toxic form of Aβ toward smaller aggregates, referred to as "soluble oligomers." These oligomers have become one of the prime suspects for involvement in the early oxidative damage that is evident in this disease. This raises the question whether or not Aβ fibrils are actually "inert tombstones" present at the end of the aggregation process. Here we show that, when Aβ(1-42) aggregates, including fibrils, are bound to Cu(II) ions, they retain their redox activity and are able to degrade hydrogen peroxide (H2O2) with the formation of hydroxyl radicals and the consequent oxidation of the peptide (detected by formation of carbonyl groups). We find that this ability increases as the Cu(II):peptide ratio increases and is accompanied by changes in aggregate morphology, as determined by atomic force microscopy. When aggregates are prepared in the copresence of Cu(II) and Zn(II) ions, the ratio of Cu(II):Zn(II) becomes an important factor in the degeneration of H2O2, the formation of carbonyl groups in the peptide, and in aggregate morphology. We believe, therefore, that Aβ fibrils can destroy H2O2 and generate damaging hydroxyl radicals and, so, are not necessarily inert end points.
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mayes
authors.affiliation: Department of Physics, Faculty of Science and Technology, Lancaster University, Lancaster LA1 4YQ, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Tinker-Mill
authors.affiliation: Department of Physics, Faculty of Science and Technology, Lancaster University, Lancaster LA1 4YQ, United Kingdom.
authors.forename: Oleg
authors.initials: O
authors.lastname: Kolosov
authors.affiliation: Lancaster Environment Centre, Lancaster University, Lancaster LA1 4YQ, United Kingdom.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, United Kingdom.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Tabner
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, United Kingdom. Electronic address: d.allsop@lancaster.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Allsop
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D003300:Copper; D006861:Hydrogen Peroxide
keywords: Alzheimer Disease; Copper Ions; Free Radicals; Hydrogen Peroxide; Oxidative Stress; Peptide Aggregation; Reactive Oxygen Species (ROS); Zinc Ions; β-Amyloid