Amyloid-β Fibrillogenesis Seeded by Interface-Induced Peptide Misfolding and Self-Assembly

The amphipathicity of the natively unstructured amyloid-beta (A beta 40) peptide may play an important role in its aggregation into beta-sheet rich fibrils, which is linked to the pathogenesis of Alzheimer's disease. Using the air/subphase interface as a model interface, we characterized A beta's surface activity and its conformation, assembly, and morphology at the interface. A beta readily adsorbed to the air/subphase interface to form a 20 A thick film and showed a critical micelle concentration of similar to 120 nM. A beta adsorbed at the air/subphase exhibited in-plane ordering that gave rise to Bragg peaks in grazing-incidence x-ray diffraction measurements. Analysis of the peaks showed that the air/subphase interface induced A beta to fold into a beta-sheet conformation and to self-assemble into similar to 100 A-sized ordered clusters. The formation of these clusters at the air/subphase interface was not affected by pH, salts, or the presence of sucrose or urea, which are known to stabilize or denature native proteins, suggesting that interface-driven A beta misfolding and assembly are strongly favored. Furthermore, A beta at the interface seeded the growth of fibrils in the bulk with a distinct morphology compared to those formed by homogeneous nucleation. Our results indicate that interface-induced A beta misfolding may serve as a heterogeneous, nucleation-controlled aggregation mechanism for A beta fibrillogenesis in vivo.