Abstract: Determining the pathological role of amyloids in amyloid-associated diseases such as Alzheimer's disease will require a method for determining the dynamic distributions in size and shape of amyloid oligomers with high resolution. Here, we explored the potential of resistive-pulse sensing through lipid bilayer-coated nanopores to measure the size of individual amyloid-β oligomers directly in solution and without chemical modification. This method classified individual amyloid-β aggregates as spherical oligomers, protofibrils, or mature fibers and made it possible to account for the large heterogeneity of amyloid-β aggregate sizes. The approach revealed the distribution of protofibrillar lengths as well as the average cross-sectional area of protofibrils and fibers.
Impact: We show that nanopore-based resistive pulse recordings made it possible to characterize the size and shape of unlabeled aggregates of Alzheimer's disease-relevant amyloids in solution. The particular strength of nanopore sensing lies in its ability to characterize a large number of individual aggregates. This capability for single particle analysis is required to characterize Aβ aggregates with a wide-ranging, dynamic heterogeneity in size and shape as well as to correlate cytotoxicity and pathogenic mechanisms with aggregate sizes and shapes.
Journal: Paper accepted to ACS Nano, DOI: 10.1021/nn300542q
Submitted by Michael Mayer, Associate Professor of Biomedical Engineering and Associate Professor of Chemical Engineering, College of Engineering.