Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers

A beta 42 oligomers play key roles in the pathogenesis of Alzheimer disease, but their structures remain elusive partly due to their transient nature. Here, we show that A beta 42 in a fusion construct can be trapped in a stable oligomer state, which recapitulates characteristics of prefibrillar A beta 42 oligomers and enables us to establish their detailed structures. Site-directed spin labeling and electron paramagnetic resonance studies provide structural restraints in terms of side chain mobility and intermolecular distances at all 42 residue positions. Using these restraints and other biophysical data, we present a novel atomic-level oligomer model. In our model, each A beta 42 protein forms a single beta-sheet with three beta-strands in an antiparallel arrangement. Each beta-sheet consists of four A beta 42 molecules in a head-to-tail arrangement. Four beta-sheets are packed together in a face-to-back fashion. The stacking of identical segments between different beta-sheets within an oligomer suggests that prefibrillar oligomers may interconvert with fibrils via strand rotation, wherein beta-strands undergo an similar to 90 degrees rotation along the strand direction. This work provides insights into rational design of therapeutics targeting the process of interconversion between toxic oligomers and non-toxic fibrils.