Lipid membranes catalyse the fibril formation of the amyloid-β (1–42) peptide through lipid-fibril interactions that reinforce secondary pathways

Alzheimer's disease is associated with the aggregation of amyloid-β (Aβ) peptides into oligomers and fibrils. We have explored how model lipid membranes modulate the rate and mechanisms of Aβ(1–42) self-assembly, in order to shed light on how this pathological reaction may occur in the lipid-rich environments that the peptide encounters in the brain. Using a combination of in vitro biophysical experiments and theoretical approaches, we show that zwitterionic DOPC lipid vesicles accelerate the Aβ(1–42) fibril growth rate by interacting specifically with the growing fibrils. We probe this interaction with help of a purpose-developed Förster resonance energy transfer assay that monitors the proximity between a fibril-specific dye and fluorescent lipids in the lipid vesicle membrane. To further rationalise these findings we use mathematical models to fit the aggregation kinetics of Aβ(1–42) and find that lipid vesicles alter specific mechanistic steps in the aggregation reaction; they augment monomer-dependent secondary nucleation at the surface of existing fibrils and facilitate monomer-independent catalytic processes consistent with fibril fragmentation. We further show that DOPC vesicles have no effect on primary nucleation. This finding is consistent with experiments showing that Aβ(1–42) monomers do not directly bind to the lipid bilayer. Taken together, our results show that plain lipid membranes with charge and composition that is representative of outer cell membranes can significantly augment autocatalytic steps in the self-assembly of Aβ(1–42) into fibrils. This new insight suggests that strategies to reduce fibril-lipid interactions in the brain may have therapeutic value. [Display omitted] •Lipid membranes bind to Aβ(1–42) fibrils and thereby catalyse amyloid formation.•Lipid-fibril interactions augment secondary nucleation steps in the aggregation.•Lipid membranes also facilitate monomer-independent fibril fragmentation.•Aβ(1–42) monomers do not directly interact with lipid membranes.•A new FRET assay is presented and applied to study the fibril-lipid interaction.