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Role of Aromatic Side Chains in Amyloid β-Protein Aggregation.

Cukalevski, Risto LU ; Boland, Barry; Frohm, Birgitta LU ; Thulin, Eva LU ; Walsh, Dominic and Linse, Sara LU (2012) In ACS Chemical Neuroscience 3(12). p.1008-1016
Abstract
Aggregation of the amyloid β-protein (Aβ) is believed to be involved in Alzheimer's disease pathogenesis. Here we have investigated the importance of the aromatic rings at positions 19 and 20 for the aggregation rate and mechanism by substituting phenylalanine with leucine. Aggregation kinetics were monitored as a function of time and peptide concentration by thioflavin T (ThT) fluorescence, the aggregation equilibrium by sedimentation assay, structural changes using circular dichroism spectroscopy and the presence of fibrillar material was detected with cryo-transmission electron microscopy. All peptides convert from monomer to amyloid fibrils in a concentration-dependent manner. Substituting F19 with leucine results in a peptide that... (More)
Aggregation of the amyloid β-protein (Aβ) is believed to be involved in Alzheimer's disease pathogenesis. Here we have investigated the importance of the aromatic rings at positions 19 and 20 for the aggregation rate and mechanism by substituting phenylalanine with leucine. Aggregation kinetics were monitored as a function of time and peptide concentration by thioflavin T (ThT) fluorescence, the aggregation equilibrium by sedimentation assay, structural changes using circular dichroism spectroscopy and the presence of fibrillar material was detected with cryo-transmission electron microscopy. All peptides convert from monomer to amyloid fibrils in a concentration-dependent manner. Substituting F19 with leucine results in a peptide that aggregates significantly slower than the wild type, while substitution of F20 produces a peptide that aggregates faster. The effects of the two substitutions are additive, since simultaneous substitution of F19 and F20 produces a peptide with aggregation kinetics intermediate between F19L and F20L. Our results suggest that the aromatic side-chain of F19 favors nucleation of the aggregation process and may be an important target for therapeutic intervention. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
ACS Chemical Neuroscience
volume
3
issue
12
pages
1008 - 1016
publisher
The American Chemical Society
external identifiers
  • wos:000312564400005
  • pmid:23259036
  • scopus:84871285635
ISSN
1948-7193
DOI
10.1021/cn300073s
language
English
LU publication?
yes
id
706b8f33-38b4-41b7-adc6-22b0da983b98 (old id 3346984)
date added to LUP
2013-01-07 12:20:13
date last changed
2017-11-12 03:42:23
@article{706b8f33-38b4-41b7-adc6-22b0da983b98,
  abstract     = {Aggregation of the amyloid β-protein (Aβ) is believed to be involved in Alzheimer's disease pathogenesis. Here we have investigated the importance of the aromatic rings at positions 19 and 20 for the aggregation rate and mechanism by substituting phenylalanine with leucine. Aggregation kinetics were monitored as a function of time and peptide concentration by thioflavin T (ThT) fluorescence, the aggregation equilibrium by sedimentation assay, structural changes using circular dichroism spectroscopy and the presence of fibrillar material was detected with cryo-transmission electron microscopy. All peptides convert from monomer to amyloid fibrils in a concentration-dependent manner. Substituting F19 with leucine results in a peptide that aggregates significantly slower than the wild type, while substitution of F20 produces a peptide that aggregates faster. The effects of the two substitutions are additive, since simultaneous substitution of F19 and F20 produces a peptide with aggregation kinetics intermediate between F19L and F20L. Our results suggest that the aromatic side-chain of F19 favors nucleation of the aggregation process and may be an important target for therapeutic intervention.},
  author       = {Cukalevski, Risto and Boland, Barry and Frohm, Birgitta and Thulin, Eva and Walsh, Dominic and Linse, Sara},
  issn         = {1948-7193},
  language     = {eng},
  number       = {12},
  pages        = {1008--1016},
  publisher    = {The American Chemical Society},
  series       = {ACS Chemical Neuroscience},
  title        = {Role of Aromatic Side Chains in Amyloid β-Protein Aggregation.},
  url          = {http://dx.doi.org/10.1021/cn300073s},
  volume       = {3},
  year         = {2012},
}