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.

Amyloids are self-assembled protein architectures implicated in dozens of misfolding diseases. These assemblies appear to emerge through a "selection" of specific conformational "strains" which nucleate and propagate within cells to cause disease. The short Abeta(16-22) peptide, which includes the central core of the Alzheimer's disease Abeta peptide, generates an amyloid fiber which is morphologically indistinguishable from the full-length peptide fiber, but it can also form other morphologies under distinct conditions. Here we combine spectroscopic and microscopy analyses that reveal the subtle atomic-level differences that dictate assembly of two conformationally pure Abeta(16-22) assemblies, amyloid fibers and nanotubes, and define the minimal repeating unit for each assembly.

Fundamental questions about the relative arrangement of the beta-sheet arrays within amyloid fibrils remain central to both its structure and the mechanism of self-assembly. Recent computational analyses suggested that sheet-to-sheet lamination was limited by the length of the strand. On the basis of this hypothesis, a short seven-residue segment of the Alzheimer's disease-related Abeta peptide, Abeta(16-22), was allowed to self-assemble under conditions that maintained the basic amphiphilic character of Abeta. Indeed, the number increased over 20-fold to 130 laminates, giving homogeneous bilayer structures that supercoil into long robust nanotubes. Small-angle neutron scattering and X-ray scattering defined the outer and inner radii of the nanotubes in solution to contain a 44-nm inner cavity with 4-nm-thick walls. Atomic force microscopy and transmission electron microscopy images further confirmed these homogeneous arrays of solvent-filled nanotubes arising from a flat rectangular bilayer, 130 nm wide x 4 nm thick, with each bilayer leaflet composed of laminated beta-sheets. The corresponding backbone H-bonds are along the long axis, and beta-sheet lamination defines the 130-nm bilayer width. This bilayer coils to give the final nanotube. Such robust and persistent self-assembling nanotubes with positively charged surfaces of very different inner and outer curvature now offer a unique, robust, and easily accessible scaffold for nanotechnology.