title: Synthetic toxic Aβ1-42oligomers can assemble in different morphologies.
abstract: Alzheimer's disease is the most common neurodegenerative disease associated with aggregation of Aβ peptides. Aβ toxicity is mostly related to the capacity of intermediate oligomers to disrupt membrane integrity. We previously expressed Aβ1-42in a eukaryotic cellular system and selected synthetic variants on their sole toxicity. The most toxic mutant G37C forms stable oligomers.
  
  
  
  Different biophysical methods (Fluorescence spectroscopy, cross-linking, mass spectrometry (MS), Small Angle X-ray Scattering (SAXS), Atomic Force Microscopy (AFM), Transmission Electron Microscopy (TEM), calcein leakage) were used.
  
  
  
  The oligomers are mostly populated by a 14mers resulting from the packing of homodimers. These homodimers come from the formation of a disulfide bridge between two monomers. This link stabilizes the multimers and prevents the assembly into amyloid fibrils. These oligomers affect the membrane integrity. The reduction of disulfide bonds leads to a rearrangement and redirects assembly of Aβ amyloid fibrils.
  
  
  
  The toxic synthetic AβG37Cmutant can assemble into an amyloid of unusual morphology through the formation of anti-parallel β-sheets. This pathway involves the formation of oligomers resulting from the arrangement of Aβ dimers linked by covalent di-sulfide link, being these oligomers harmful for the membranes.
  
  
  
  The capacity to produce large amount of stable oligomers without additional detergents or extrinsic cross-linkers allow further structural and biophysical studies to understand their capacity to assemble and disrupt the membranes, a key event in Alzheimer's disease.
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, IBGC CNRS UMR 5095, Université de Bordeaux, 1 rue Camille Saint Saëns, 33077 Bordeaux Cedex, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Bobo
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université de Bordeaux, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chaignepain
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université de Bordeaux, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Henry
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, IBGC CNRS UMR 5095, Université de Bordeaux, 1 rue Camille Saint Saëns, 33077 Bordeaux Cedex, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Vignaud
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université de Bordeaux, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Alfred
authors.initials: A
authors.lastname: Améadan
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université de Bordeaux, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Marchal
authors.affiliation: Univ. Pau & Pays Adour, CNRS, Institut des Sciences Analytiques et de Physico-chimie pour l'Environnement et les Matériaux, IPREM, UMR 5254, Technopole Hélioparc, 2 avenue du Président Pierre Angot, 64053 Pau Cedex 09, France.
authors.forename: Enora
authors.initials: E
authors.lastname: Prado
authors.affiliation: Diamond Light Source Ltd., Didcot, Oxfordshire OX11 ODE, UK.
authors.forename: James
authors.initials: J
authors.lastname: Doutch
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université de Bordeaux, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Schmitter
authors.affiliation: Univ. Pau & Pays Adour, CNRS, Institut des Sciences Analytiques et de Physico-chimie pour l'Environnement et les Matériaux, IPREM, UMR 5254, Technopole Hélioparc, 2 avenue du Président Pierre Angot, 64053 Pau Cedex 09, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Nardin
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université de Bordeaux, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lecomte
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université de Bordeaux, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France. Electronic address: christophe.cullin@u-bordeaux.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cullin
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D018625:Microscopy, Atomic Force / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D053838:Scattering, Small Angle; D013050:Spectrometry, Fluorescence / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments
keywords: Amyloid; Aβ(1–42); Membrane; Oligomers