Protofibril–Fibril Interactions Inhibit Amyloid Fibril Assembly by Obstructing Secondary Nucleation

Amyloid‐β peptides (Aβ) assemble into both rigid amyloid fibrils and metastable oligomers termed AβO or protofibrils. In Alzheimer's disease, Aβ fibrils constitute the core of senile plaques, but Aβ protofibrils may represent the main toxic species. Aβ protofibrils accumulate at the exterior of senile plaques, yet the protofibril–fibril interplay is not well understood. Applying chemical kinetics and atomic force microscopy to the assembly of Aβ and lysozyme, protofibrils are observed to bind to the lateral surfaces of amyloid fibrils. When utilizing Aβ variants with different critical oligomer concentrations, the interaction inhibits the autocatalytic proliferation of amyloid fibrils by secondary nucleation on the fibril surface. Thus, metastable oligomers antagonize their replacement by amyloid fibrils both by competing for monomers and blocking secondary nucleation sites. The protofibril—fibril interaction governs their temporal evolution and potential to exert specific toxic activities.