Solid State NMR Reveals a pH-dependent Antiparallel β-Sheet Registry in Fibrils Formed by a β-Amyloid Peptide

We report solid state nuclear magnetic resonance (NMR) measurements that probe the supramolecular organization of β-sheets in the cross-β motif of amyloid fibrils formed by residues 11–25 of the β-amyloid peptide associated with Alzheimerʹs disease (Aβ11–25). Fibrils were prepared at pH 7.4 and pH 2.4. The solid state NMR data indicate that the central hydrophobic segment of Aβ11–25 (sequence LVFFA) adopts a β-strand conformation and participates in antiparallel β-sheets at both pH values, but that the registry of intermolecular hydrogen bonds is pH-dependent. Moreover, both registries determined for Aβ11–25 fibrils are different from the hydrogen bond registry in the antiparallel β-sheets of Aβ16–22 fibrils at pH 7.4 determined in earlier solid state NMR studies. In all three cases, the hydrogen bond registry is highly ordered, with no detectable “registry-shift” defects. These results suggest that the supramolecular organization of β-sheets in amyloid fibrils is determined by a sensitive balance of multiple side-chain–side-chain interactions. Recent structural models for Aβ11–25 fibrils based on X-ray fiber diffraction data are inconsistent with the solid state NMR data at both pH values.