Aβ Oligomer Dissociation Is Catalyzed by Fibril Surfaces

Oligomeric assemblies consisting of only a few protein
subunits
are key species in the cytotoxicity of neurodegenerative disorders,
such as Alzheimer’s and Parkinson’s diseases. Their
lifetime in solution and abundance, governed by the balance of their
sources and sinks, are thus important determinants of disease. While
significant advances have been made in elucidating the processes that
govern oligomer production, the mechanisms behind their dissociation
are still poorly understood. Here, we use chemical kinetic modeling
to determine the fate of oligomers formed in vitro and discuss the
implications for their abundance in vivo. We discover that oligomeric
species formed predominantly on fibril surfaces, a broad class which
includes the bulk of oligomers formed by the key Alzheimer’s
disease-associated Aβ peptides, also dissociate overwhelmingly
on fibril surfaces, not in solution as had previously been assumed.
We monitor this “secondary nucleation in reverse” by
measuring the dissociation of Aβ42 oligomers in the presence
and absence of fibrils via two distinct experimental methods. Our
findings imply that drugs that bind fibril surfaces to inhibit oligomer
formation may also inhibit their dissociation, with important implications
for rational design of therapeutic strategies for Alzheimer’s
and other amyloid diseases.