title: Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation.
abstract: We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) peptide in our Drosophila model system. These data point to an important pathogenic role for iron in Alzheimer disease. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. We confirm that chelation of iron protects the fly from the harmful effects of Aβ. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ toxicity but only if the metal is present throughout the aggregation process. These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease.
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors.forename: Beinan
authors.initials: B
authors.lastname: Liu
authors.forename: Aileen
authors.initials: A
authors.lastname: Moloney
authors.forename: Sarah
authors.initials: S
authors.lastname: Meehan
authors.forename: Kyle
authors.initials: K
authors.lastname: Morris
authors.forename: Sally E
authors.initials: SE
authors.lastname: Thomas
authors.forename: Louise C
authors.initials: LC
authors.lastname: Serpell
authors.forename: Robert
authors.initials: R
authors.lastname: Hider
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Marciniak
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Damian C
authors.initials: DC
authors.lastname: Crowther
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004331:Drosophila melanogaster; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D005293:Ferritins; D007501:Iron