Increasing the amphiphilicity of an amyloidogenic peptide changes the β-sheet structure in the fibrils from antiparallel to parallel

Solid-state NMR measurements have been reported for four peptides derived from beta-amyloid peptide Abeta(1-42): Abeta(1-40), Abeta(10-35), Abeta(16-22), and Abeta(34-42). Of these, the first two are predicted to be amphiphilic and were reported to form parallel beta-sheets, whereas the latter two peptides appear nonamphiphilic and adopt an antiparallel beta-sheet organization. These results suggest that amphiphilicity may be significant in determining fibril structure. Here, we demonstrate that acylation of Abeta(16-22) with octanoic acid increases its amphiphilicity and changes the organization of fibrillar beta-sheet from antiparallel to parallel. Electron microscopy, Congo Red binding, and one-dimensional C-13 NMR measurements demonstrate that octanoyl-Abeta(16-22) forms typical amyloid fibrils. Based on the stability of monolayers at the air-water interface, octanoyl-Abeta(16-22) is more amphiphilic than Abeta(16-22). Measurements of C-13-C-13 and N-15-C-3 nuclear magnetic dipole-dipole couplings in isotopically labeled fibril samples, using the constant-time finite-pulse radiofrequency-driven recoupling (fpRFDR-CT) and rotational echo double resonance (REDOR) solid-state NMR techniques, demonstrate that octanoyl-Abeta(16-22) fibrils are composed of parallel beta-sheets, whereas Abeta(16-22) fibrils are composed of antiparallel beta-sheets. These data demonstrate that amphiphilicity is critical in determining the structural organization of beta-sheets in the amyloid fibril. This work also shows that all amyloid fibrils do not share a common supramolecular structure, and suggests a method for controlling the structure of amyloid fibrils.