Propagating structure of Alzheimer's β-amyloid(10-35) is parallel β-sheet with residues in exact register

The pathognomonic plaques of Alzheimer's disease are composed primarily of the 39- to 43-aa beta-amyloid (A beta) peptide. Crosslinking of A beta peptides by tissue transglutaminase (tTg) indicates that Gln(15) of one peptide is proximate to Lys(16) of another in aggregated A beta. sere se report how the fibril structure is resolved by mapping interstrand distances in this core region of the A beta peptide chain with solid-state NMR. Isotopic substitution provides the source points for measuring distances in aggregated A beta. Peptides containing a single carbonyl C-13 label at Gln15, 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 Angstrom. Analysis of these data establish that this central core of A beta consists of a parallel beta-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 beta fibril is a hydrogen-bonded, parallel beta-sheet defining the long asis of the A beta fibril propagation.