Antiparallel β-Sheet Structure within the C-Terminal Region of 42-Residue Alzheimer's Amyloid-β Peptides When They Form 150-kDa Oligomers

Understanding the molecular structures of amyloid-beta (A beta) oligomers and underlying assembly pathways will advance our understanding of Alzheimer's disease (AD) at the molecular level. This understanding could contribute to disease prevention, diagnosis, and treatment strategies, as oligomers play a central role in AD pathology. We have recently presented a procedure for production of 150-kDa oligomeric samples of A beta(1-42) (the 42-residue variant of the A beta peptide) that are compatible with solid-state nuclear magnetic resonance (NMR) analysis, and we have shown that these oligomers and amyloid fibrils differ in intermolecular arrangement of beta-strands. Here we report new solid-state NMR constraints that indicate antiparallel intermolecular alignment of beta-strands within the oligomers. Specifically, 150-kDa A beta(1-42) oligomers with uniform C-13 and N-15 isotopic labels at 132, M35, G37, and V40 exhibit beta-strand secondary chemical shifts in 2-dimensional (2D) finite-pulse radiofrequency-driven recoupling NMR spectra, spatial proximities between 132 and V40 as well as between M35 and G37 in 2D dipolar-assisted rotational resonance spectra, and close proximity between M35 H-alpha and G37 H-alpha in 2D CHHC spectra. Furthermore, 2D dipolar-assisted rotational resonance analysis of an oligomer sample prepared with 30% labeled peptide indicates that the 132-V40 and M35-G37 contacts are between residues on different molecules. We employ molecular modeling to compare the newly derived experimental constraints with previously proposed geometries for arrangement of A beta molecules into oligomers. (C) 2015 Elsevier Ltd. All rights reserved.