A Hexameric Peptide Barrel as Building Block of Amyloid-β Protofibrils

Oligomeric and protofibrillar aggregates formed by the amyloid-A beta peptide (A beta) are believed to be involved in the pathology of Alzheimer's disease. Central to Alzheimer pathology is also the fact that the longer A beta(42) peptide is more prone to aggregation than the more prevalent A beta(40). Detailed structural studies of A beta oligomers and protofibrils have been impeded by aggregate heterogeneity and instability. We previously engineered a variant of A beta that forms stable protofibrils and here we use solid-state NMR spectroscopy and molecular modeling to derive a structural model of these. NMR data are consistent with packing of residues 16 to 42 of A beta protomers into hexameric barrel-like oligomers within the protofibril. The core of the oligomers consists of all residues of the central and C-terminal hydrophobic regions of A beta, and hairpin loops extend from the core. The model accounts for why A beta(42) forms oligomers and protofibrils more easily than A beta(40).