Increasing the Amphiphilicity of an Amyloidogenic Peptide Changes the β-Sheet Structure in the Fibrils from Antiparallel to Parallel

Abstract

Solid-state NMR measurements have been reported for four peptides derived from β-amyloid peptide Aβ(1-42): Aβ(1-40), Aβ(10-35), Aβ(16-22), and Aβ(34-42). Of these, the first two are predicted to be amphiphilic and were reported to form parallel β-sheets, whereas the latter two peptides appear nonamphiphilic and adopt an antiparallel β-sheet organization. These results suggest that amphiphilicity may be significant in determining fibril structure. Here, we demonstrate that acylation of Aβ(16-22) with octanoic acid increases its amphiphilicity and changes the organization of fibrillar β-sheet from antiparallel to parallel. Electron microscopy, Congo Red binding, and one-dimensional 13C NMR measurements demonstrate that octanoyl-Aβ(16-22) forms typical amyloid fibrils. Based on the stability of monolayers at the air-water interface, octanoyl-Aβ(16-22) is more amphiphilic than Aβ(16-22). Measurements of 13C-13C and 15N-13C 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-Aβ(16-22) fibrils are composed of parallel β-sheets, whereas Aβ(16-22) fibrils are composed of antiparallel β-sheets. These data demonstrate that amphiphilicity is critical in determining the structural organization of β-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.