title: Interaction of Aβ(1-42) amyloids with lipids promotes "off-pathway" oligomerization and membrane damage.
abstract: The toxicity of amyloids, as Aβ(1-42) involved in Alzheimer disease, is a subject under intense scrutiny. Many studies link their toxicity to the existence of various intermediate structures prior to fiber formation and/or their specific interaction with membranes. In this study we focused on the interaction between membrane models and Aβ(1-42) peptides and variants (L34T, mG37C) produced in E. coli and purified in monomeric form. We evaluated the interaction of a toxic stable oligomeric form (oG37C) with membranes as comparison. Using various biophysical techniques as fluorescence and plasmon waveguide resonance, we clearly established that the oG37C interacts strongly with membranes leading to its disruption. All the studied peptides destabilized liposomes and accumulated slowly on the membrane (rate constant 0.02 min(-1)). Only the oG37C exhibited a particular pattern of interaction, comprising two steps: the initial binding followed by membrane reorganization. Cryo-TEM was used to visualize the peptide effect on liposome morphologies. Both oG37C and mG37C lead to PG membrane fragmentation. The PG membrane promotes peptide oligomerization, implicated in membrane disruption. WT (Aβ(1-42)) also perturbs liposome organization with membrane deformation rather than disruption. For all the peptides studied, their interaction with the membranes changes their fibrillization process, with less fibers and more small aggregates being formed. These studies allowed to establish, a correlation between toxicity, fiber formation, and membrane disruption.
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.forename: Hélène
authors.initials: H
authors.lastname: Vignaud
authors.forename: Claude
authors.initials: C
authors.lastname: Bobo
authors.forename: Marion
authors.initials: M
authors.lastname: Decossas
authors.forename: Oliver
authors.initials: O
authors.lastname: Lambert
authors.forename: Etienne
authors.initials: E
authors.lastname: Harte
authors.forename: Isabel D
authors.initials: ID
authors.lastname: Alves
authors.forename: Christophe
authors.initials: C
authors.lastname: Cullin
authors.forename: Sophie
authors.initials: S
authors.lastname: Lecomte
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002463:Cell Membrane Permeability; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry*; D010715:Phosphatidylglycerols / Q000737:chemistry*; D055503:Protein Multimerization; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D053835:Unilamellar Liposomes; C075222:amyloid beta-protein (1-42); C051388:1,2-dioleoyl-sn-glycero-3-phosphoglycerol; C017251:1,2-oleoylphosphatidylcholine