Oligomeric and protofibrillar aggregates formed by the amyloid-β peptide (Aβ) are believed to be involved in the pathology of Alzheimer's disease. Central to Alzheimer pathology is also the fact that the longer Aβ42 peptide is more prone to aggregation than the more prevalent Aβ40 . Detailed structural studies of Aβ oligomers and protofibrils have been impeded by aggregate heterogeneity and instability. We previously engineered a variant of Aβ 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 Aβ 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 Aβ, and hairpin loops extend from the core. The model accounts for why Aβ42 forms oligomers and protofibrils more easily than Aβ40 .

An exclusive label: 15N{17O} REAPDOR NMR was used to validate intermolecular C17O⋅⋅⋅H15N hydrogen bonding in Ac‐Aβ(16–22)‐NH2 (see scheme) and Aβ(11–25) amyloid fibrils, which are associated with Alzheimer's disease, by selectively labeling them with 17O and 15N. This method was effective for confirming the structure of these fibrils, and could be useful for a number of other biological samples.

Oligomeric and protofibrillar aggregates formed by the amyloid-b peptide (Ab) are believed to be involved in the pathology of Alzheimers disease. Central to Alzheimer pathology is also the fact that the longer Ab 42 peptide is more prone to aggregation than the more prevalent Ab 40 . Detailed structural studies of Ab oligomers and protofibrils have been impeded by aggregate heterogeneity and instability. We previously engineered a variant of Ab 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 Ab 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 Ab, and hairpin loops extend from the core. The model accounts for why Ab 42 forms oligomers and protofibrils more easily than Ab 40 .