title: Copper abolishes the beta-sheet secondary structure of preformed amyloid fibrils of amyloid-beta(42).
abstract: The observation of the co-deposition of metals and amyloid-beta(42) (Abeta(42)) in brain tissue in Alzheimer's disease prompted myriad investigations into the role played by metals in the precipitation of this peptide. Copper is bound by monomeric Abeta(12) and upon precipitation of the copper-peptide complex thereby prevents Abeta(42) from adopting a beta-sheet secondary structure. Copper is also bound by beta-sheet conformers of Abeta(42), and herein we have investigated how this interaction affects the conformation of the precipitated peptide. Copper significantly reduced the thioflavin T fluorescence of aged, fibrillar Abeta(42) with, for example, a 20-fold excess of the metal resulting in a ca 90% reduction in thioflavin T fluorescence. Transmission electron microscopy showed that copper significantly reduced the quantities of amyloid fibrils while Congo red staining and polarized light demonstrated a copper-induced abolition of apple-green birefringence. Microscopy under cross-polarized light also revealed the first observation of spherulites of Abeta(42). The size and appearance of these amyloid structures were found to be very similar to spherulites identified in Alzheimer's disease tissue. The combined results of these complementary methods strongly suggested that copper abolished the beta-sheet secondary structure of pre-formed, aged amyloid fibrils of Abeta(42). Copper may protect against the presence of beta-sheets of Abeta(42) in vivo, and its binding by fibrillar Abeta(42) could have implications for Alzheimer's disease therapy.
authors.affiliation: The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire ST5 5BG, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: House
authors.forename: Matthew
authors.initials: M
authors.lastname: Mold
authors.forename: Joanna
authors.initials: J
authors.lastname: Collingwood
authors.forename: Alex
authors.initials: A
authors.lastname: Baldwin
authors.forename: Steven
authors.initials: S
authors.lastname: Goodwin
authors.forename: Christopher
authors.initials: C
authors.lastname: Exley
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000187:drug effects* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D052160:Benzothiazoles; D001718:Birefringence; D003224:Congo Red; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D005456:Fluorescent Dyes; D006801:Humans; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013844:Thiazoles
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D010455:Peptides; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D003224:Congo Red; D003300:Copper