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Specific binding of an engineered β-cyclodextrin dimer to the amyloid β peptide modulates the peptide aggregation process
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
URN: urn:nbn:se:su:diva-60343OAI: oai:DiVA.org:su-60343DiVA: diva2:434550
Available from: 2011-08-15 Created: 2011-08-15 Last updated: 2011-08-19Bibliographically approved
In thesis
1. NMR studies on interactions between the amyloid β peptide and selected molecules
Open this publication in new window or tab >>NMR studies on interactions between the amyloid β peptide and selected molecules
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease is an incurable neurodegenerative disorder linked to the amyloid β (Aβ) peptide, a 38-43 residue peptide. The detailed molecular disease mechanism(s) is (are) unknown, but oligomeric Aβ structures are proposed to be involved.

In common for the papers in this thesis is interactions; interactions between Aβ(1-40) and selected molecules and metal ions. The purpose has been to find out more about the structural states that Aβ can adopt, in particular the β-sheet state, which probably is linked to the oligomeric structures. The methods used have been nuclear magnetic resonance (NMR), circular dichroism (CD) and fluorescence spectroscopy using Thioflavin T (ThT).

Upon addition of SDS/LiDS detergent or Congo red (CR) to Aβ(1-40), the initial random coil/PII-helix state was transformed into β-sheet and, in the case of detergent, a final α-helical state. In contrast to SDS/LiDS and CR, the dimeric Affibody molecule locks monomeric Aβ(1-40) in a β-hairpin state. It was found that by truncating the flexible N-terminal end of the Affibody molecule its affinity to Aβ was improved. The aggregation of Aβ(1-40) was further studied in the presence of a β-cyclodextrin dimer by a kinetic assay using ThT. Although having a weak dissociation constant in the millimolar range, the β-cyclodextrin dimer modified the aggregation pathways of Aβ.

Finally Aβ(1-40) was studied in presence of Cu2+ and Zn2+ at physiological and low pH. Cu2+ was observed to maintain its specific binding to Aβ when decreasing the pH to 5.5 while Zn2+ behaved differently. This could be of importance in the Alzheimer’s disease brain in which the environment can become acidic due to inflammation.       

In conclusion the results show that Aβ(1-40) is very sensitive to its environment, responding by adopting different conformations and aggregating in aqueous solutions. The β-sheet state is induced by varying molecules with different properties, properties that govern the final Aβ state.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2011. 59 p.
Keyword
Amyloid β peptide, Alzheimer's disease, Aggregation, Oligomer, Amyloid, Interaction, Nuclear Magnetic Resonance Spectroscopy, Circular Dichroism Spectroscopy, Thioflavin T, Detergent, Congo red, Affibody, Cyclodextrin dimer, Metal ion
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-60346 (URN)978-91-7447-325-4 (ISBN)
Public defence
2011-10-07, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
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Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 5: Manuscript.Available from: 2011-09-15 Created: 2011-08-15 Last updated: 2011-09-02Bibliographically approved

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