Synthetic toxic Aß 1–42 oligomers can assemble in different morphologies

DOI: 10.1016/j.bbagen.2017.03.001

Authors: Claude Bobo (Université de Bordeaux) , Stéphane Chaignepain (Université de Bordeaux) , Sarah Henry (Université de Bordeaux) , Hélène Vignaud (Université de Bordeaux) , Alfred Améadan (Université de Bordeaux) , Christelle Marchal (Université de Bordeaux) , Enora Prado (Univ. Pau & Pays Adour) , James Doutch (Diamond Light Source) , Jean-marie Schmitter (Université de Bordeaux) , Corinne Nardin (Univ. Pau & Pays Adour) , Sophie Lecomte (Université de Bordeaux) , Christophe Cullin (Université de Bordeaux)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochimica Et Biophysica Acta (bba) - General Subjects

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 151

Abstract: Background Alzheimer's disease is the most common neurodegenerative disease associated with aggregation of Aβ peptides. Aß toxicity is mostly related to the capacity of intermediate oligomers to disrupt membrane integrity. We previously expressed Aß1–42 in a eukaryotic cellular system and selected synthetic variants on their sole toxicity. The most toxic mutant G37C forms stable oligomers. Methods 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. Results The oligomers are mostly populated by a 14 mers 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 Aß amyloid fibrils. Conclusion The toxic synthetic AßG37C 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 Aß dimers linked by covalent di-sulfide link, being these oligomers harmful for the membranes. General Significance 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.

Journal Keywords: Amyloid; Aß1–42; membrane; oligomers

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: B21-High Throughput SAXS

Added On: 09/03/2017 08:49

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