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

Jin Kim, Adrian Muresan, Ka Yee C Lee, Regina M. Murphy

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)2888-2898
Number of pages11
JournalProtein Science
Volume13
Issue number11
DOIs
StatePublished - Nov 2004

Fingerprint

Amyloid
Urea
Modulation
Kinetics
Agglomeration
Growth
Poisons
Oligomers
Elongation
Alzheimer Disease
Deposits
Peptides

Keywords

  • β-amyloid
  • Amyloid
  • Atomic force microscopy
  • Light scattering
  • Peptide aggregation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Urea modulation of β-amyloid fibril growth : Experimental studies and kinetic models. / Kim, Jin; Muresan, Adrian; Lee, Ka Yee C; Murphy, Regina M.

In: Protein Science, Vol. 13, No. 11, 11.2004, p. 2888-2898.

Research output: Contribution to journalArticle

Kim, Jin ; Muresan, Adrian ; Lee, Ka Yee C ; Murphy, Regina M. / Urea modulation of β-amyloid fibril growth : Experimental studies and kinetic models. In: Protein Science. 2004 ; Vol. 13, No. 11. pp. 2888-2898.
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