Lipid membranes catalyse the fibril formation of the amyloid-? (1–42) peptide through lipid-fibril interactions that reinforce secondary pathways
Artikel i vetenskaplig tidskrift, 2017

Alzheimer's disease is associated with the aggregation of amyloid-? (A?) peptides into oligomers and fibrils. We have explored how model lipid membranes modulate the rate and mechanisms of A?(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 A?(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 A?(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 A?(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 A?(1–42) into fibrils. This new insight suggests that strategies to reduce fibril-lipid interactions in the brain may have therapeutic value.

amyloid-?

aggregation kinetics

lipid vesicles

fibril-lipid interaction

DOPC

Alzheimer's Disease

Författare

David Lindberg

Chalmers, Biologi och bioteknik, Kemisk biologi

Emelie Vilhelmsson Wesén

Chalmers, Biologi och bioteknik, Kemisk biologi

Johan Björkeroth

Chalmers, Biologi och bioteknik, Kemisk biologi

Sandra Rocha

Chalmers, Biologi och bioteknik, Kemisk biologi

Elin Esbjörner Winters

Chalmers, Biologi och bioteknik, Kemisk biologi

Biochimica et Biophysica Acta - Biomembranes

0005-2736 (ISSN)

Vol. 1859 10 1921-1929

Ämneskategorier

Fysikalisk kemi

DOI

10.1016/j.bbamem.2017.05.012

PubMed

28564579