Amyloid-beta fibrillogenesis seeded by interface-induced peptide misfolding and self-assembly.
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.
Chi
Eva Y
EY
Department of Chemical and Nuclear Engineering, Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico, USA.
Frey
Shelli L
SL
Winans
Amy
A
Lam
Kin Lok H
KL
Kjaer
Kristian
K
Majewski
Jaroslaw
J
Lee
Ka Yee C
KY
D000682:Amyloid / Q000009:adverse effects / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000009:adverse effects* / Q000737:chemistry; D016564:Amyloid beta-Protein Precursor; D001665:Binding Sites; D002942:Circular Dichroism / Q000379:methods; D008051:Lipid Bilayers / Q000494:pharmacology; D018625:Microscopy, Atomic Force / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000009:adverse effects* / Q000494:pharmacology; D058255:Protease Nexins; D011487:Protein Conformation; D017510:Protein Folding / Q000187:drug effects*; D057165:Proteostasis Deficiencies / Q000209:etiology*; D011956:Receptors, Cell Surface; D013499:Surface Properties
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008051:Lipid Bilayers; D010446:Peptide Fragments; D010455:Peptides; D058255:Protease Nexins; D011956:Receptors, Cell Surface