Solid-state NMR analysis of the β-strand orientation of the protofibrils of amyloid β-protein

Highlights: ► The supramolecular structure of Aβ42 protofibrils was analyzed by solid-state NMR. ► The Ala-21 residue in the Aβ42 protofibrils is included in a slightly disordered β-strand. ► The Aβ42 protofibrils do not form intermolecular in-register parallel β-sheets. -- Abstract: Alzheimer's disease (AD) is caused by abnormal deposition (fibrillation) of a 42-residue amyloid β-protein (Aβ42) in the brain. During the process of fibrillation, the Aβ42 takes the form of protofibrils with strong neurotoxicity, and is thus believed to play a crucial role in the pathogenesis of AD. To elucidate the supramolecular structure of the Aβ42 protofibrils, the intermolecular proximity of the Ala-21 residues in the Aβ42 protofibrils was analyzed by 13C–13C rotational resonance experiments in the solid state. Unlike the Aβ42 fibrils, an intermolecular 13C–13C correlation was not found in the Aβ42 protofibrils. This result suggests that the β-strands of the Aβ42 protofibrils are not in an in-register parallel orientation. Aβ42 monomers would assemble to form protofibrils with the β-strand conformation, then transform into fibrils by forming intermolecular parallel β-sheets.