Steady, Symmetric, and Reversible Growth and Dissolution of Individual Amyloid-β Fibrils.

Abstract

Oligomers and fibrils of the amyloid-β (Aβ) peptide are implicated in the pathology of Alzheimer's disease. Here, we monitor the growth of individual Aβ40 fibrils by time-resolved in situ atomic force microscopy and thereby directly measure fibril growth rates. The measured growth rates in a population of fibrils that includes both single protofilaments and bundles of filaments are independent of the fibril thickness, indicating that cooperation between adjacent protofilaments does not affect incorporation of monomers. The opposite ends of individual fibrils grow at similar rates. In contrast to the "stop-and-go" kinetics that has previously been observed for amyloid-forming peptides, growth and dissolution of the Aβ40 fibrils are relatively steady for peptide concentration of 0-10 μM. The fibrils readily dissolve in quiescent peptide-free solutions at a rate that is consistent with the microscopic reversibility of growth and dissolution. Importantly, the bimolecular rate coefficient for the association of a monomer to the fibril end is significantly smaller than the diffusion limit, implying that the transition state for incorporation of a monomer into a fibril is associated with a relatively high free energy.