Journal of Molecular Biology

This study examines the effect of seeding with ex vivo Aβ amyloid fibrils on the fibril morphology in vitro.

Seeded fibrils are right-hand twisted and show a peptide fold that corresponds to the one in the seeds.

The twist and peptide fold of seeded fibrils differ from unseeded fibrils.

Upon multiple rounds of seeding, the propagation of the seed structure loses efficiency and de novo nucleated fibril structures emerge.

These findings imply a competition between seed extension and de novo nucleation in seeded samples.

Aβ amyloid fibrils from Alzheimer’s brain tissue are polymorphic and structurally different from typical in vitro formed Aβ fibrils. Here, we show that brain-derived (ex vivo) fibril structures can be proliferated by seeding in vitro. The proliferation reaction is only efficient for one of the three abundant ex vivo Aβ fibril morphologies, which consists of two peptide stacks, while the inefficiently proliferated fibril morphologies contain four or six peptide stacks. In addition to the seeded fibril structures, we find that de novo nucleated fibril structures can emerge in seeded samples if the seeding reaction is continued over multiple generations. These data imply a competition between de novo nucleation and seed extension and suggest further that seeding favours the outgrowth of fibril morphologies that contain fewer peptide stacks.

aggregation

amyloid beta

cryo-electron microscopy

prion

protein misfolding

contrast transfer function

cryo-electron microscopy

ethylenediaminetetraacetic acid

Fourier Shell Correlation

maltose binding protein

root mean square deviation

tris(hydroxymethyl)aminomethane

© 2024 The Authors. Published by Elsevier Ltd.