Amyloid-Beta(1-42)Oligomer Models Developed Using Combined Solid State Nmr And Sequence Specific Hydroxyl Radical Footprinting Data

Increasing evidence suggests that soluble aggregates of amyloid-β (Aβ) are the pathogenic species in Alzheimeru0027s disease (AD). However, detailed structural information on these species remains scarce due to low levels of endogenous Aβ oligomers and uncertainties surrounding current in vitro model systems. Herein, we describe a hydroxyl radical footprinting (HRF) study of Aβ42 monomers, dimers, and specially prepared stable and homogeneous oligomers. Specific side chain solvent accessibilities of individual residues in the folded and aggregated forms of Aβ42 are measured with respect to the same residues of Aβ42 in a fully exposed reference state. These data provide residue specific side chain solvent accessibility protection factors and are used in complement with biophysical characterizations and ss-NMR analyses of the same systems. Results are discussed in the context of proposed NMR models of Aβ oligomers with implications towards further development of therapeutic and diagnostic strategies.