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

Human PrP (huPrP) is a high-affinity receptor for oligomeric amyloid beta (A beta) protein aggregates. Binding of A beta oligomers to membrane-anchored huPrP has been suggested to trigger neurotoxic cell signaling in Alzheimer's disease, while an N-terminal soluble fragment of huPrP can sequester A beta oligomers and reduce their toxicity. Synthetic oligomeric A beta species are known to be heterogeneous, dynamic, and transient, rendering their structural investigation particularly challenging. Here, using huPrP to preserve A beta oligomers by coprecipitating them into large heteroassemblies, we investigated the conformations 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 two C-terminal a-helices. For A beta(1-42) oligomers in complex with huPrP, secondary chemical shifts reveal 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-strand-rich conformers. Taken together, our results reveal structural changes in huPrP upon binding to A beta oligomers that suggest a role of the C terminus of huPrP in cell signaling. Trapping A beta(1-42) oligomers by binding to huPrP has proved to be a useful tool for studying the structure of these highly heterogeneous beta-strand-rich assemblies.