Self-Assembly of β-Amyloid 42 Is Retarded by Small Molecular Ligands at the Stage of Structural Intermediates

Abstract

Assemblyof the amyloid-β peptide (Aβ) into fibrils and its deposition in distinct brain areas is considered responsible for the pathogenesis of Alzheimer's disease (AD). Thus, inhibition of fibril assembly is a potential strategy for therapeutic intervention. Electron cryomicroscopy was used to monitor the initial, native assembly structure of Aβ42. In addition to the known fibrillar intermediates, a nonfibrillar, polymeric sheet-like structure was identified. A temporary sequence of supramolecular structures was revealed with (i) polymeric Aβ42 sheets during the onset of assembly, inversely related to the appearance of (ii) fibril intermediates, which again are time-dependently replaced by (iii) mature fibrils. A cell-based primary screening assay was used to identify compounds that decrease Aβ42-induced toxicity. Hit compounds were further assayed for binding to Aβ42, radical scavenger activity, and their influence on the assembly structure of Aβ42. One compound, Ro 90-7501, was found to efficiently retard mature fibril formation, while extended polymeric Aβ42 sheets and fibrillar intermediates are accumulated. Ro 90-7501 may serve as a prototypic inhibitor for Aβ42 fibril formation and as a tool for studying the molecular mechanism of fibril assembly.