Structural details of amyloid beta oligomers in complex with human prion protein as revealed by solid-state MAS NMR spectroscopy

Abstract

Human PrP (huPrP) is a high-affinity receptor for oligomeric A{beta}. Synthetic oligomeric A{beta} species are known to be heterogeneous, dynamic and transient, rendering their structural investigation particularly challenging. Here, we used huPrP to preserve A{beta} oligomers by co-precipitating them into large hetero-assemblies to investigate the conformation of A{beta}(1-42) oligomers and huPrP in the complex by solid-state MAS NMR spectroscopy. The disordered N-terminal region of huPrP becomes immobilized in the complex and therefore visible in dipolar spectra without adopting chemical shifts characteristic of a regular secondary structure. Most of the well-defined C-terminal part of huPrP is part of the rigid complex, and solid-state NMR spectra suggest a loss in regular secondary structure in the last two -helices. For A{beta}(1-42) oligomers in complex with huPrP, secondary chemical shifts reveal a substantial {beta}-strand content. Importantly, not all A{beta}(1-42) molecules within the complex have identical conformations. Comparison with the chemical shifts of synthetic A{beta} fibrils suggests that the A{beta} oligomer preparation represents a heterogeneous mixture of {beta}-strand-rich assemblies, of which some have the potential to evolve and elongate into different fibril polymorphs, reflecting a general propensity of A{beta} to adopt variable {beta}-structure conformers.