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

• Published in: Biophysical journal 2010-05, Vol.98 (10), p.2299-2308
• Main Authors: Chi, Eva Y, Frey, Shelli L, Winans, Amy, Lam, Kin Lok H, Kjaer, Kristian, Majewski, Jaroslaw, Lee, Ka Yee C
• Format: Article
• Language: English
• ISSN: 0006-3495
• DOI: 10.1016/j.bpj.2010.01.056

The amphipathicity of the natively unstructured amyloid-b (Ab40) peptide may play an important role in its aggregation into b-sheet rich fibrils, which is linked to the pathogenesis of Alzheimer's disease. Using the air/subphase interface as a model interface, we characterized Ab's surface activity and its conformation, assembly, and morphology at the interface. Ab readily adsorbed to the air/subphase interface to form a 20 Aa thick film and showed a critical micelle concentration of [not, vert, similar]120 nM. Ab 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 Ab to fold into a b-sheet conformation and to self-assemble into [not, vert, similar]100 Aa-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 Ab misfolding and assembly are strongly favored. Furthermore, Ab 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 Ab misfolding may serve as a heterogeneous, nucleation-controlled aggregation mechanism for Ab fibrillogenesis in vivo.