A Hidden Structural Transition Accompanies the Progression of Amyloid-Beta Oligomers to Mature Fibrils

Abstract

Toxicity of Aβ aggregates, suspected to be the key to Alzheimer's disease, is strongly size dependent. Toxicity is expected to be related to structure, which possibly evolves with size. However, structural studies have suggested that the structured parts of the peptide remain rather similar between the oligomers and the mature fibrils, and are dominated by long beta sheet regions. This presents a major puzzle. Here we time-resolve the structural evolution accompanying the growth of the oligomers into fibrils (following a recently developed strategy1). We probe the structure using solid state NMR, IR and Raman spectroscopy, and TEM. We find a previously hidden transition which preserves the well-known beta-sheet character of the peptide. This transition is consistent with a backbone twist, which changes an intramolecular hydrogen bonded anti-parallel beta-sheet to an inter-molecular hydrogen bonded one. At the atomic level, this transition is concurrent with the formation of a salt bridge between D23 and K28, which is a key non-local contact, observed in many of the fibrillar Aβ structures reported so far. Molecular dynamic simulations lend support to these findings. Interestingly, a similar backbone architecture has also been found for the oligomers in lipid bilayers, using SERS and lipid-coated nanoparticles2. Our observation provides a structural basis for understanding the putative change of toxicity associated with the progressive aggregation of small Aβ oligomers.1) Sarkar et al., Angew. Chem. Int. Ed. Engl. 2014, http://dx.doi.org/10.1002/anie.2014026362) Bhowmik et al., ACS Nano, http://dx.doi.org/10.1021/acsnano.5b03175