title: Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide β-amyloid (1-42).
abstract: For decades, a link between increased levels of iron and areas of Alzheimer's disease (AD) pathology has been recognized, including AD lesions comprised of the peptide β-amyloid (Aβ). Despite many observations of this association, the relationship between Aβ and iron is poorly understood. Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aβ(1-42) and synthetic iron(III), reminiscent of ferric iron stores in the brain. We report Aβ to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aβ-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aβ, enabling the redox cycling of the iron. These results demonstrate the ability of Aβ to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD. These interactions between Aβ and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies.
authors.affiliation: Institute for Science and Technology in Medicine, Keele University, , Stoke-on-Trent, Staffordshire ST4 7QB, UK.
authors.forename: J
authors.initials: J
authors.lastname: Everett
authors.forename: E
authors.initials: E
authors.lastname: Céspedes
authors.forename: L R
authors.initials: LR
authors.lastname: Shelford
authors.forename: C
authors.initials: C
authors.lastname: Exley
authors.forename: J F
authors.initials: JF
authors.lastname: Collingwood
authors.forename: J
authors.initials: J
authors.lastname: Dobson
authors.forename: G
authors.initials: G
authors.lastname: van der Laan
authors.forename: C A
authors.initials: CA
authors.lastname: Jenkins
authors.forename: E
authors.initials: E
authors.lastname: Arenholz
authors.forename: N D
authors.initials: ND
authors.lastname: Telling
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D005296:Ferrous Compounds; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D007501:Iron
keywords: Alzheimer's disease; X-ray absorption; redox; wüstite; β-amyloid