Amyloid-beta fibrillogenesis seeded by interface-induced peptide misfolding and self-assembly

Biophys J. 2010 May 19;98(10):2299-308. doi: 10.1016/j.bpj.2010.01.056.


The amphipathicity of the natively unstructured amyloid-beta (Abeta40) 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 Abeta's surface activity and its conformation, assembly, and morphology at the interface. Abeta readily adsorbed to the air/subphase interface to form a 20 A thick film and showed a critical micelle concentration of approximately 120 nM. Abeta 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 Abeta to fold into a beta-sheet conformation and to self-assemble into approximately 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 Abeta misfolding and assembly are strongly favored. Furthermore, Abeta 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 Abeta misfolding may serve as a heterogeneous, nucleation-controlled aggregation mechanism for Abeta fibrillogenesis in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid / adverse effects
  • Amyloid / chemistry*
  • Amyloid beta-Peptides / adverse effects*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Protein Precursor
  • Binding Sites
  • Circular Dichroism / methods
  • Lipid Bilayers / pharmacology
  • Microscopy, Atomic Force / methods
  • Peptide Fragments / pharmacology*
  • Peptides / adverse effects*
  • Peptides / pharmacology
  • Protease Nexins
  • Protein Conformation
  • Protein Folding / drug effects*
  • Proteostasis Deficiencies / etiology*
  • Receptors, Cell Surface
  • Surface Properties


  • Amyloid
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Lipid Bilayers
  • Peptide Fragments
  • Peptides
  • Protease Nexins
  • Receptors, Cell Surface