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Specific Binding of a beta-Cyclodextrin Dimer to the Amyloid beta Peptide Modulates the Peptide Aggregation Process

Wahlstrom, Anna; Cukalevski, Risto LU ; Danielsson, Jens; Jarvet, Jueri; Onagi, Hideki; Rebek, Julius Jr.; Linse, Sara LU and Graslund, Astrid (2012) In Biochemistry 51(21). p.4280-4289
Abstract
Alzheimer's disease involves progressive neuronal loss. Linked to the disease is the amyloid beta (A beta) peptide, a 38-43-amino acid peptide found in extracellular amyloid plaques in the brain. Cyclodextrins are nontoxic, cone-shaped oligosaccharides with a hydrophilic exterior and a hydrophobic cavity making them suitable hosts for aromatic guest molecules in water. beta-Cyclodextrin consists of seven alpha-D-glucopyranoside units and has been shown to reduce the level of fibrillation and neurotoxicity of A beta. We have studied the interaction between A beta and a beta-cyclodextrin dimer, consisting of two beta-cyclodextrin monomers connected by a flexible linker. The beta-cyclodextrin monomer has been found to interact with A... (More)
Alzheimer's disease involves progressive neuronal loss. Linked to the disease is the amyloid beta (A beta) peptide, a 38-43-amino acid peptide found in extracellular amyloid plaques in the brain. Cyclodextrins are nontoxic, cone-shaped oligosaccharides with a hydrophilic exterior and a hydrophobic cavity making them suitable hosts for aromatic guest molecules in water. beta-Cyclodextrin consists of seven alpha-D-glucopyranoside units and has been shown to reduce the level of fibrillation and neurotoxicity of A beta. We have studied the interaction between A beta and a beta-cyclodextrin dimer, consisting of two beta-cyclodextrin monomers connected by a flexible linker. The beta-cyclodextrin monomer has been found to interact with A beta(1-40) at sites Y10, F19, and/or F20 with a dissociation constant (K-D) of 3.9 +/- 2.0 mM. Here H-1-N-15 and H-1-C-13 heteronuclear single-quantum correlation nuclear magnetic resonance (NMR) spectra show that in addition, the beta-cyclodextrin monomer and dimer bind to the histidines. NMR translational diffusion experiments reveal the increased affinity of the beta-cyclodextrin dimer (apparent K-D of 1.1 +/- .5 mM) for A beta(1-40) compared to that of the beta-cyclodextrin monomer. Kinetic aggregation experiments based on thioflavin T fluorescence indicate that the dimer at 0.05-5 mM decreases the lag time of A beta aggregation, while a concentration of 10 mM increases the lag time. The beta-cyclodextrin monomer at a high concentration decreases the lag time of the aggregation. We conclude that cyclodextrin monomers and dimers have specific, modulating effects on the A beta(1-40) aggregation process. Transmission electron microscopy shows that the regular fibrillar aggregates formed by A beta(1-40) alone are replaced by a major fraction of amorphous aggregates in the presence of the beta-cyclodextrin dimer. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemistry
volume
51
issue
21
pages
4280 - 4289
publisher
The American Chemical Society
external identifiers
  • wos:000304492500006
  • scopus:84861591086
ISSN
0006-2960
DOI
10.1021/bi300341j
language
English
LU publication?
yes
id
59f39517-9416-4b10-83cb-ada6f0ae7ad0 (old id 2799789)
date added to LUP
2012-06-25 12:34:39
date last changed
2017-10-22 03:02:52
@article{59f39517-9416-4b10-83cb-ada6f0ae7ad0,
  abstract     = {Alzheimer's disease involves progressive neuronal loss. Linked to the disease is the amyloid beta (A beta) peptide, a 38-43-amino acid peptide found in extracellular amyloid plaques in the brain. Cyclodextrins are nontoxic, cone-shaped oligosaccharides with a hydrophilic exterior and a hydrophobic cavity making them suitable hosts for aromatic guest molecules in water. beta-Cyclodextrin consists of seven alpha-D-glucopyranoside units and has been shown to reduce the level of fibrillation and neurotoxicity of A beta. We have studied the interaction between A beta and a beta-cyclodextrin dimer, consisting of two beta-cyclodextrin monomers connected by a flexible linker. The beta-cyclodextrin monomer has been found to interact with A beta(1-40) at sites Y10, F19, and/or F20 with a dissociation constant (K-D) of 3.9 +/- 2.0 mM. Here H-1-N-15 and H-1-C-13 heteronuclear single-quantum correlation nuclear magnetic resonance (NMR) spectra show that in addition, the beta-cyclodextrin monomer and dimer bind to the histidines. NMR translational diffusion experiments reveal the increased affinity of the beta-cyclodextrin dimer (apparent K-D of 1.1 +/- .5 mM) for A beta(1-40) compared to that of the beta-cyclodextrin monomer. Kinetic aggregation experiments based on thioflavin T fluorescence indicate that the dimer at 0.05-5 mM decreases the lag time of A beta aggregation, while a concentration of 10 mM increases the lag time. The beta-cyclodextrin monomer at a high concentration decreases the lag time of the aggregation. We conclude that cyclodextrin monomers and dimers have specific, modulating effects on the A beta(1-40) aggregation process. Transmission electron microscopy shows that the regular fibrillar aggregates formed by A beta(1-40) alone are replaced by a major fraction of amorphous aggregates in the presence of the beta-cyclodextrin dimer.},
  author       = {Wahlstrom, Anna and Cukalevski, Risto and Danielsson, Jens and Jarvet, Jueri and Onagi, Hideki and Rebek, Julius Jr. and Linse, Sara and Graslund, Astrid},
  issn         = {0006-2960},
  language     = {eng},
  number       = {21},
  pages        = {4280--4289},
  publisher    = {The American Chemical Society},
  series       = {Biochemistry},
  title        = {Specific Binding of a beta-Cyclodextrin Dimer to the Amyloid beta Peptide Modulates the Peptide Aggregation Process},
  url          = {http://dx.doi.org/10.1021/bi300341j},
  volume       = {51},
  year         = {2012},
}