Cryo-EM Analysis of the Effect of Seeding with Brain-derived Ab Amyloid Fibrils

Ab amyloid fibrils from Alzheimer's brain tissue are polymorphic and structurally different from typical in vitro formed Ab 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 Ab 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. (c) 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).