In vitro, β-amyloid (Aβ) peptides form polymorphic fibrils, with molecular structures that depend on growth conditions, plus various oligomeric and protofibrillar aggregates. Detailed structural information about Aβ assemblies in the human brain has been lacking. Here, we investigate structures of brain-derived Aβ fibrils, using seeded fibril growth from brain extract and data from solid state nuclear magnetic resonance and electron microscopy. Experiments on tissue from two Alzheimer’s disease (AD) patients with distinct clinical histories indicate a single predominant 40-residue Aβ (Aβ40) fibril structure in each patient, but different structures in the two patients. A molecular structural model developed for Aβ40 fibrils from one patient reveals features that distinguish in vivo from in vitro fibrils. The data suggest that fibrils in the brain may spread from a single nucleation site, that structural variations may correlate with variations in AD, and that structure-specific amyloid imaging agents may be an important future goal.

The pathognomonic plaques of Alzheimer's disease are composed primarily of the 39-to 43-aa ␤-amyloid (A␤) peptide. Crosslinking of A␤ peptides by tissue transglutaminase (tTg) indicates that Gln 15 of one peptide is proximate to Lys 16 of another in aggregated A␤. Here we report how the fibril structure is resolved by mapping interstrand distances in this core region of the A␤ peptide chain with solid-state NMR. Isotopic substitution provides the source points for measuring distances in aggregated A␤. Peptides containing a single carbonyl 13 C label at Gln 15 , Lys 16 , Leu 17 , or Val 18 were synthesized and evaluated by NMR dipolar recoupling methods for the measurement of interpeptide distances to a resolution of 0.2 Å. Analysis of these data establish that this central core of A␤ consists of a parallel ␤-sheet structure in which identical residues on adjacent chains are aligned directly, i.e., in register. Our data, in conjunction with existing structural data, establish that the A␤ fibril is a hydrogen-bonded, parallel ␤-sheet defining the long axis of the A␤ fibril propagation.

No abstract

We report constraints on the supramolecular structure of amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (A beta(1-40)) obtained from solid-state nuclear magnetic resonance (NMR) measurements of intermolecular dipole-dipole couplings between (13)C labels at 11 carbon sites in residues 2 through 39. The measurements are carried out under magic-angle spinning conditions, using the constant-time finite-pulse radiofrequency-driven recoupling (fpRFDR-CT) technique. We also present one-dimensional (13)C magic-angle spinning NMR spectra of the labeled A beta(1-40) samples. The fpRFDR-CT data reveal nearest-neighbor intermolecular distances of 4.8 +/- 0.5 A for carbon sites from residues 12 through 39, indicating a parallel alignment of neighboring peptide chains in the predominantly beta-sheet structure of the amyloid fibrils. The one-dimensional NMR spectra indicate structural order at these sites. The fpRFDR-CT data and NMR spectra also indicate structural disorder in the N-terminal segment of A beta(1-40), including the first nine residues. These results place strong constraints on any molecular-level structural model for full-length beta-amyloid fibrils.