title: Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge.
abstract: Amyloid-beta peptide (Abeta) is pivotal to the pathogenesis of Alzheimer disease. Here we report the formation of a toxic Abeta-Cu2+ complex formed via a histidine-bridged dimer, as observed at Cu2+/peptide ratios of >0.6:1 by EPR spectroscopy. The toxicity of the Abeta-Cu2+ complex to cultured primary cortical neurons was attenuated when either the pi -or tau-nitrogen of the imidazole side chains of His were methylated, thereby inhibiting formation of the His bridge. Toxicity did not correlate with the ability to form amyloid or perturb the acyl-chain region of a lipid membrane as measured by diphenyl-1,3,5-hexatriene anisotropy, but did correlate with lipid peroxidation and dityrosine formation. 31P magic angle spinning solid-state NMR showed that Abeta and Abeta-Cu2+ complexes interacted at the surface of a lipid membrane. These findings indicate that the generation of the Abeta toxic species is modulated by the Cu2+ concentration and the ability to form an intermolecular His bridge.
authors.affiliation: Department of Pathology, Centre for Neuroscience, and School of Chemistry, University of Melbourne, Victoria 3010, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Smith
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Smith
authors.forename: Cyril C
authors.initials: CC
authors.lastname: Curtain
authors.forename: John F
authors.initials: JF
authors.lastname: Boas
authors.forename: John R
authors.initials: JR
authors.lastname: Pilbrow
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Ciccotosto
authors.forename: Tong-Lay
authors.initials: TL
authors.lastname: Lau
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Tew
authors.forename: Keyla
authors.initials: K
authors.lastname: Perez
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: Simon C
authors.initials: SC
authors.lastname: Drew
authors.forename: Frances
authors.initials: F
authors.lastname: Separovic
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D004578:Electron Spin Resonance Spectroscopy; D006639:Histidine / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D006639:Histidine; D003300:Copper