Paravastu, Anant K.

Synchrotron based hydroxyl radical footprinting (HRF) was employed to study the formation of Aβ 42 oligomers, believed to be the neurotoxic species in Alzheimer's disease. Rates of oxidative modification for seventeen individual residues (F4, Y10, H13, H14, L17, F19, F20, V24, K28, I31, I32, M35, V36, V39, V40, I41) were determined for monomer, 2‐4mer, and oligomer Aβ 42 relative to intrinsic rates of modification determined for the same residues in fragment peptide. The ratio of measured and intrinsic rates reveals protection from hydroxyl radical attack due to reduced side chain solvent accessibility for structured Aβ 42 . Protection observed in the intrinsically disordered Aβ 42 monomer is consistent with transient C‐terminal β‐strand formation and partial folding in the hydrophobic core region. Our results also reveal dimerization (and further assembly) contacts that are consistent both with oligomer C‐terminal antiparallel β‐sheet formation previously indicated from published solid state NMR work studies and newly detected N‐terminal structure.

The brains of Alzheimer’s disease (AD) patients contain numerous amyloid plaques that are diagnostic of the disease. The plaques are primarily composed of the amyloidogenic peptides proteins Aβ40 and Aβ42, which are derived by the processing of the amyloid pre-cursor protein (APP) by two proteases called β-secretase and γ-secretase. Aβ42 differs from Aβ40 in having two additional hydrophobic amino acids, ILE and ALA, at the C-terminus. A small percentage of AD is autosomal dominant (ADAD) and linked either to the genes for the presenilins, which are part of γ-secretase, or APP. Because ADAD shares most pathogenic features with widespread late-onset AD, Aβ peptides have become the focus of AD research. Fibrils formed by the aggregation of these peptides are the major component of plaques and were initially targeted in AD therapy. However, the fact that the abundance of plaques does not correlate well with cognitive decline in AD patients has led investigators to examine smaller Aβ aggregates called oligomers. The low levels and heterogeneity of Aβ oligomers have made the determination of their structures difficult, but recent structure determinations of oligomers either formed or initiated in detergents have been achieved. We report here on the structures of these oligomers and suggest how they may be involved in AD.