Quantitative analysis of co-oligomer formation by amyloid-beta peptide isoforms.

ABSTRACT: Multiple isoforms of aggregation-prone proteins are present under physiological conditions and have the propensity to assemble into co-oligomers with different properties from self-oligomers, but this process has not been quantitatively studied to date. We have investigated the amyloid-? (A?) peptide, associated with Alzheimer's disease, and the aggregation of its two major isoforms, A?40 and A?42, using a statistical mechanical modelling approach in combination with in vitro single-molecule fluorescence measurements. We find that at low concentrations of A?, corresponding to its physiological abundance, there is little free energy penalty in forming co-oligomers, suggesting that the formation of both self-oligomers and co-oligomers is possible under these conditions. Our model is used to predict the oligomer concentration and size at physiological concentrations of A? and suggests the mechanisms by which the ratio of A?42 to A?40 can affect cell toxicity. An increased ratio of A?42 to A?40 raises the fraction of oligomers containing A?42, which can increase the hydrophobicity of the oligomers and thus promote deleterious binding to the cell membrane and increase neuronal damage. Our results suggest that co-oligomers are a common form of aggregate when A? isoforms are present in solution and may potentially play a significant role in Alzheimer's disease.

SUBMITTER: Iljina M 

PROVIDER: S-EPMC4921824 | biostudies-other | 2016

REPOSITORIES: biostudies-other