Synthetic Toxic Aβ1–42 Oligomers Can Assemble in Different Morphologies



Claude Bobo2, Stéphane Chaignepain1, Sarah Henry1, Hélène Vignaud2, Alfred Améadan1, Christelle Marchal1, Enora Prado4, James Doutch3, Jean-Marie Schmitter1, Corinne Nardin4, Sophie Lecomte1, and Christophe Cullin1


  1. Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université de Bordeaux, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France
  2. Institut de Biochimie et Génétique Cellulaires, IBGC CNRS UMR 5095, Université de Bordeaux, 1 rue Camille Saint Saëns, 33077 Bordeaux cedex, France
  3. Diamond Light Source Ltd., Didcot, Oxfordshire, OX11 ODE, UK
  4. 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


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 Aβ1-42 in 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 AβG37C mutant 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.

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Aβ samples (monomers or oligomers) were analyzed using a MALDI TOF/TOF mass spectrometer modified with the CovalX HM2 detection system. Prior to analysis, the samples were crosslinked and then mixed with a matrix solution of sinapic acid. The mixture was placed on the MALDI target and dried. Through the MALDI analysis, the researchers were able to determine that AβG37C forms covalent homodimers that are not dissociated when being analyzed using mass spectrometry. Thus, the results prove that there is an S-S bond linkage between two monomers of G37C in the purified fraction that corresponds to oG37C.


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