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

The amphipathicity of the natively unstructured amyloid-β (Aβ40) peptide may play an important role in its aggregation into β-sheet rich fibrils, which is linked to the pathogenesis of Alzheimer's disease. Using the air/subphase interface as a model interface, we characterized Aβ's surface activity and its conformation, assembly, and morphology at the interface. Aβ readily adsorbed to the air/subphase interface to form a 20 Å thick film and showed a critical micelle concentration of ∼120 nM. Aβ 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 Aβ to fold into a β-sheet conformation and to self-assemble into ∼100 Å-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 Aβ misfolding and assembly are strongly favored. Furthermore, Aβ 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 Aβ misfolding may serve as a heterogeneous, nucleation-controlled aggregation mechanism for Aβ fibrillogenesis in vivo.