Specific Binding of a beta-Cyclodextrin Dimer to the Amyloid beta Peptide Modulates the Peptide Aggregation Process
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2799789
- author
- Wahlstrom, Anna ; Cukalevski, Risto LU ; Danielsson, Jens ; Jarvet, Jueri ; Onagi, Hideki ; Rebek, Julius Jr. ; Linse, Sara LU and Graslund, Astrid
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Biochemistry
- volume
- 51
- issue
- 21
- pages
- 4280 - 4289
- publisher
- The American Chemical Society (ACS)
- 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
- 2016-04-01 09:55:49
- date last changed
- 2023-11-09 07:43:57
@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 (ACS)}},
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}},
doi = {{10.1021/bi300341j}},
volume = {{51}},
year = {{2012}},
}