BACKGROUND: Alzheimer's disease is the most common neurodegenerative disease associated with aggregation of Abeta peptides. Abeta toxicity is mostly related to the capacity of intermediate oligomers to disrupt membrane integrity. We previously expressed Abeta1-42 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 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 Abeta amyloid fibrils. CONCLUSION: The toxic synthetic AbetaG37C mutant can assemble into an amyloid of unusual morphology through the formation of anti-parallel beta-sheets. This pathway involves the formation of oligomers resulting from the arrangement of Abeta 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.< Réduire