Toxic peptide oligomers are predecessors of amyloid plaques [with video]

At physiologically low peptide concentrations, formation of amyloid fibrils is a peculiar two-step process. Disordered protein oligomers, often considered toxic, are found to be crucial on-pathway species for amyloid aggregation under cellular conditions. Formation of peptide oligomers and hence, amyloid fibrils, is controlled by the strength of nonspecific attractions between peptides in solution, whose weakening may be crucial in preventing the formation of amyloid plaques.

HFSP Cross-Disciplinary Fellow Andela Saric and colleagues
authored on Fri, 05 December 2014

The assembly of normally soluble proteins into large fibrils, known as amyloid aggregation, is associated with a range of pathologies, including Alzheimer’s and Parkinson’s diseases. It is increasingly believed that the disordered protein oligomers that accompany the amyloid aggregation, but not the fully grown fibers, are the main toxic agents associated with the aberrant processes. However, whether these oligomers are necessary for amyloid fibril assembly or just a toxic byproduct remains unresolved.

Figure: Simple computer model of amyloid aggregation at physiological concentrations. Left panel: Solution of amyloidogenic peptides. A peptide oligomer is circled in red. Right panel: Peptides aggregated in amyloid fibrils.

Amyloid aggregation appears to be a generic property of polypeptide chains unless their native state is particularly stable. Because of its ubiquitousness, the process is believed to be governed by generic interactions between monomers, such as the hydrophobic interactions and hydrogen bonding, rather than by the specific details of the sequence. This allows us to use a simple coarse-grained model of an amyloidogenic peptide, which we guide by atomistic simulations of Alzheimer’s Abeta1-42 peptide. The great advantage of such a model is that it is sufficiently cheap to allow us to reach large system-sizes and long time-scales, while exploring a wide range of peptide concentrations and interpeptide interactions.

The most relevant regime for Abeta peptides under physiological conditions is the regime of low peptide concentrations (micro- and nanomolar). Our simulations show that in this case nucleation of amyloid fibrils can only be achieved if there are appreciable attractive interactions between soluble monomers. Such nonspecific attractions favor the formation of long-lived peptide oligomers, in which subsequent fibril nucleation can take place. Amyloid aggregation is then necessarily a two-state process: oligomer formation being the first step, and fibril nucleation within oligomers being the second.

Peptide oligomers help nucleation of fibrils by facilitating the conversion of peptides from their soluble form into the beta-sheet prone form, characteristic of the amyloid cross-beta-sheet structure. We find that there is an optimal oligomeric size for amyloid nucleation and that classical nucleation theory cannot be applied to this process. Remarkably, at low peptide concentrations, nucleation typically does not proceed through the most prevalent oligomers but rather, through an oligomer with a size that is only observed as a result of rare fluctuations. As a consequence, such species will be hard to capture experimentally, although their presence is required for nucleation to take place.

Amyloid nucleation through the two-step mechanism is easier the stronger the interactions between soluble peptides are. Formation of oligomers and hence, amyloid fibrils, is controlled by the strength of these nonspecific attractions between peptides in solution, whose weakening may be crucial in preventing amyloid aggregation.


Crucial role of nonspecific interactions in amyloid nucleation. Anđela Šarić, Yassmine C. Chebaro, Tuomas P. J. Knowles, and Daan Frenkel. PNAS (2014)  doi: 10.1073/pnas.1410159111.

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