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Urea modulation of -amyloid fibril growth: Experimental studies and kinetic models

¹ Department of Chemical and Biological Engineering, University of Wisconsin, Madison, Wisconsin 53706, USA
² Department of Physics and ³ Department of Chemistry, Institute for Biophysical Dynamics, and the James Franck Institute, University of Chicago, Chicago, Illinois 60637, USA

(RECEIVED May 3, 2004; FINAL REVISION July 21, 2004; ACCEPTED July 22, 2004)

Aggregation of -amyloid (A) 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 A, recent evidence supports the hypothesis that A oligomers, intermediates in the fibrillogenic pathway, are the dominant toxic species. In this work we used urea to reduce the driving force for A 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, -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 A 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.

Keywords: amyloid; -amyloid; light scattering; atomic force microscopy; peptide aggregation

Abbreviations: A, -amyloid • AFM, atomic force microscopy • CD, circular dichroism • DLS, dynamic light scattering • PrP, prion protein • SEC, size exclusion chromatography.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04847404.

Reprint requests to: Regina M. Murphy, Department of Chemical and Biological Engineering, University of Wisconsin, 1415 Engineering Drive, Madison, WI 53706, USA; e-mail: murphy{at}che.wisc.edu; fax: (608) 262-5434.

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