Structural and Mechanistic Analyses of the Effects of Small Compounds on Amyloid Beta Self-Assembly

Abstract

Although the natural tendency of proteins is to acquire soluble native-like functional states, they are able to undertake alternative pathways, such as self-association into ordered insoluble amyloid fibrils. The latter are protein aggregates that share common cross-β sheet structures and give rise to various incurable disorders, such as Alzheimer's and Parkinson's diseases. The abnormal self-assembly of amyloid beta (Aβ), an intrinsically disordered peptide, into neurotoxic oligomers and fibrils is strongly associated with Alzheimer's disease, thus prompting a comprehensive search for small compounds capable of inhibiting its aggregation. Although many compounds have been reported with this effect, the mechanisms by which they act are still largely unclear. In the present study, we use Small-Angle X-Ray Scattering (SAXS) as a high-throughput tool to screen an in-house fragment-based library in an attempt to identify new potential inhibitors targeting Aβ aggregation. We follow the fibrillation process of Aβ in solution over time in order to resolve major co-exisiting species and monitor by SAXS the effect of small compounds on these species. This approach is expected to provide molecular insights into Aβ self-assembly mechanism and lead effectively to much needed new treatment options.