Urea modulation of beta-amyloid fibril growth: experimental studies and kinetic models.
Aggregation of beta-amyloid (Abeta) into fibrillar deposits is widely believed to initiate a cascade of adverse biological responses associated with Alzheimer's disease. Although it was once assumed that the mature fibril was the toxic form of Abeta, recent evidence supports the hypothesis that Abeta oligomers, intermediates in the fibrillogenic pathway, are the dominant toxic species. In this work we used urea to reduce the driving force for Abeta aggregation, in an effort to isolate stable intermediate species. The effect of urea on secondary structure, size distribution, aggregation kinetics, and aggregate morphology was examined. With increasing urea concentration, beta-sheet content and the fraction of aggregated peptide decreased, the average size of aggregates was reduced, and the morphology of aggregates changed from linear to a globular/linear mixture and then to globular. The data were analyzed using a previously published model of Abeta aggregation kinetics. The model and data were consistent with the hypothesis that the globular aggregates were intermediates in the amyloidogenesis pathway rather than alternatively aggregated species. Increasing the urea concentration from 0.4 M to 2 M decreased the rate of filament initiation the most; between 2 M and 4 M urea the largest change was in partitioning between the nonamyloid and amyloid pathways, and between 4 M and 6 M urea, the most significant change was a reduction in the rate of filament elongation.
Department of Chemical and Biological Engineering, University of Wisconsin, 1415 Engineering Drive, Madison, WI 53706, USA.
Jin Ryoun
JR
Kim
Adrian
A
Muresan
Ka Yee C
KY
Lee
Regina M
RM
Murphy
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D010316:Particle Size; D017433:Protein Structure, Secondary / Q000187:drug effects; D014508:Urea / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D014508:Urea