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

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 (13)C-(13)C rotational resonance experiments in the solid state. Unlike the Aβ42 fibrils, an intermolecular (13)C-(13)C 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.