title: An imaging and systems modeling approach to fibril breakage enables prediction of amyloid behavior.
abstract: Delineating the nanoscale properties and the dynamic assembly and disassembly behaviors of amyloid fibrils is key for technological applications that use the material properties of amyloid fibrils, as well as for developing treatments of amyloid-associated disease. However, quantitative mechanistic understanding of the complex processes involving these heterogeneous supramolecular systems presents challenges that have yet to be resolved. Here, we develop an approach that is capable of resolving the time dependence of fibril particle concentration, length distribution, and length and position dependence of fibril fragmentation rates using a generic mathematical framework combined with experimental data derived from atomic force microscopy analysis of fibril length distributions. By application to amyloid assembly of β2-microglobulin in vitro under constant mechanical stirring, we present a full description of the fibril fragmentation and growth behavior, and demonstrate the predictive power of the approach in terms of the samples' fibril dimensions, fibril load, and their efficiency to seed the growth of new amyloid fibrils. The approach developed offers opportunities to determine, quantify, and predict the course and the consequences of amyloid assembly.
authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom; Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom. Electronic address: w.f.xue@kent.ac.uk.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Xue
authors.affiliation: Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: Sheena E
authors.initials: SE
authors.lastname: Radford
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D018625:Microscopy, Atomic Force / Q000379:methods*; D008954:Models, Biological; D001613:beta 2-Microglobulin / Q000737:chemistry
chemical_list: D000682:Amyloid; D001613:beta 2-Microglobulin