Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments

Abstract

AbstractA wide range of human disorders, including Alzheimer’s disease (AD), are characterised by the aberrant formation of amyloid fibrils. Amyloid fibrils are filamentous structures characterized by the presence of a highly-ordered cross-β core. In many cases, this core structure is flanked by disordered regions, often referred to as fuzzy coat. The structural properties of fuzzy coats, and the way in which they interact with their environments, however, have not been described in full detail to date. Here, we generated the conformational ensembles of two brain-derived amyloid filaments of Aβ42, corresponding respectively to familial and sporadic forms of AD. The approach that we used, called metadynamic electron microscopy metainference (MEMMI), enabled us to provide a characterization of the transient interactions between the fuzzy coat and the cross-β core of the filaments. These calculations indicated that the familial AD filaments are less soluble than the sporadic AD filaments, and that the fuzzy coat contributes to increasing the solubility of both types of filament. In addition, by analyzing the deviations between the density maps from cryo-EM and from the MEMMI structural ensembles, we observed a slowing down in the diffusion of water and sodium ions near the surface of the filaments, offering insight into the hydration dynamics of amyloid fibrils. These results illustrate how the metainference approach can help analyse cryo-EM maps for the characterisation of the properties of amyloid fibrils.