Out-of-register parallel β-sheets and antiparallel β-sheets coexist in 150 kDa oligomers formed by Aβ(1-42)

We present solid-state NMR measurements of {beta}-strand secondary structure and inter-strand organization within a 150 kDa oligomeric aggregate of the 42-residue variant of the Alzheimers amyloid-{beta} peptide (A{beta}(1-42)). This oligomer is characterized by a structure that cannot be explained by any previously proposed model for aggregated A{beta}. We build upon our previous report of a {beta}-strand spanned by residues 30-42, which arranges into an antiparallel {beta}-sheet. New results presented here indicate that there is a second {beta}-strand formed by residues 11-24. We show negative results for NMR experiments designed to reveal antiparallel {beta}-sheets formed by this {beta}-strand. Remarkably, we show that this strand is organized into a parallel {beta}-sheet despite the co-existence of an antiparallel {beta}-sheet in the same structure. In addition, the in-register parallel {beta}-sheet commonly observed for amyloid fibril structure does not apply to residues 11-24 in the 150 kDa oligomer. Rather, we present evidence for an inter-strand registry shift of 3 residues that alternates in direction between adjacent molecules along the {beta}-sheet. We corroborated this unexpected scheme for {beta}-strand organization using multiple 2-dimensional NMR and 13C-13C dipolar recoupling experiments. Our findings indicate a previously unknown assembly pathway and inspire a suggestion as to why this aggregate does not grow to larger sizes.