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NMR studies on interactions between the amyloid β peptide and selected molecules
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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 [en]
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: urn:nbn:se:su:diva-60346ISBN: 978-91-7447-325-4 (print)OAI: oai:DiVA.org:su-60346DiVA: diva2:434596
Public defence
2011-10-07, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
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
List of papers
1. Secondary structure conversions of Alzheimer’s Aβ(1–40) peptide induced by membrane-mimicking detergents
Open this publication in new window or tab >>Secondary structure conversions of Alzheimer’s Aβ(1–40) peptide induced by membrane-mimicking detergents
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2008 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 275, no 20, 5117-5128 p.Article in journal (Refereed) Published
Abstract [en]

The amyloid β peptide (Aβ) with 39–42 residues is the major component of amyloid plaques found in brains of Alzheimer’s disease patients, and soluble oligomeric peptide aggregates mediate toxic effects on neurons. The Aβ aggregation involves a conformational change of the peptide structure to β-sheet. In the present study, we report on the effect of detergents on the structure transitions of Aβ, to mimic the effects that biomembranes may have. In vitro, monomeric Aβ(1–40) in a dilute aqueous solution is weakly structured. By gradually adding small amounts of sodium dodecyl sulfate (SDS) or lithium dodecyl sulfate to a dilute aqueous solution, Aβ(1–40) is converted to β-sheet, as observed by CD at 3 °C and 20 °C. The transition is mainly a two-state process, as revealed by approximately isodichroic points in the titrations. Aβ(1–40) loses almost all NMR signals at dodecyl sulfate concentrations giving rise to the optimal β-sheet content (approximate detergent/peptide ratio = 20). Under these conditions, thioflavin T fluorescence measurements indicate a maximum of aggregated amyloid-like structures. The loss of NMR signals suggests that these are also involved in intermediate chemical exchange. Transverse relaxation optimized spectroscopy NMR spectra indicate that the C-terminal residues are more dynamic than the others. By further addition of SDS or lithium dodecyl sulfate reaching concentrations close to the critical micellar concentration, CD, NMR and FTIR spectra show that the peptide rearranges to form a micelle-bound structure with α-helical segments, similar to the secondary structures formed when a high concentration of detergent is added directly to the peptide solution.

Keyword
amyloid β peptide, CD, NMR, oligomer, SDS
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-14837 (URN)10.1111/j.1742-4658.2008.06643.x (DOI)000259511300015 ()18786140 (PubMedID)
Available from: 2008-11-05 Created: 2008-11-05 Last updated: 2017-12-13Bibliographically approved
2. Detergent-like interaction of Congo red with the amyloid beta peptide
Open this publication in new window or tab >>Detergent-like interaction of Congo red with the amyloid beta peptide
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2010 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 49, no 7, 1358-1360 p.Article in journal (Refereed) Published
Abstract [en]

Accumulating evidence links prefibrillar oligomeric species of the amyloid beta peptide (Abeta) to cellular toxicity in Alzheimer's disease, potentially via disruption of biological membranes. Congo red (CR) affects protein aggregation. It is known to self-associate into micelle-like assemblies but still reduces the toxicity of Abeta aggregates in cell cultures and model organisms. We show here that CR interacts with Abeta(1-40) in a manner similar to that of anionic detergents. Although CR promotes beta sheet formation and peptide aggregation, it may also solubilize toxic protein species, making them less harmful to critical cellular components and thereby reducing amyloid toxicity.

Keyword
Alzheimer's disease, amyloid beta peptide, Congo red
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-51710 (URN)10.1021/bi902005t (DOI)20070125 (PubMedID)
Available from: 2011-01-12 Created: 2011-01-12 Last updated: 2017-12-11Bibliographically approved
3. N-terminal engineering of amyloid-β-binding Affibody molecules yields improved chemical synthesis and higher binding affinity
Open this publication in new window or tab >>N-terminal engineering of amyloid-β-binding Affibody molecules yields improved chemical synthesis and higher binding affinity
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2010 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 19, no 12, 2319-2329 p.Article in journal (Refereed) Published
Abstract [en]

The aggregation of amyloid-beta (A beta) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease Molecules binding with high affinity and selectivity to A beta-peptides are important tools for investigating the aggregation process An A beta-binding Affibody molecule, Z(A beta 3), has earlier been selected by phage display and shown to bind A beta(1-40) with nanomolar affinity and to inhibit A beta-peptide aggregation In this study, we create truncated functional versions of the Z(A beta 3) Affibody molecule better suited for chemical synthesis production Engineered Affibody molecules of different length were produced by solid phase peptide synthesis and allowed to form covalently linked homodimers by S-S-bridges The N-terminally truncated Affibody molecules Z(A beta 3)(12-58), Z(A beta 3)(15-58), and Z(A beta 3)(18-58) were produced in considerably higher synthetic yield than the corresponding full-length molecule Z(A beta 3)(1-58) Circular dichroism spectroscopy and surface plasmon resonance-based biosensor analysis showed that the shortest Affibody molecule, Z(A beta 3)(18-58), exhibited complete loss of binding to the A beta(1-40)-peptide, while the Z(A beta 3)(12-58) and Z(A beta 3)(15-58) Affibody molecules both displayed approximately one order of magnitude higher binding affinity to the A beta(1-40)-peptide compared to the full-length Affibody molecule Nuclear magnetic resonance spectroscopy showed that the structure of A beta(1-40) in complex with the truncated Affibody dimers is very similar to the previously published solution structure of the A beta(1-40)-peptide in complex with the full-length Z(A beta 3) Affibody molecule This indicates that the N-terminally truncated Affibody molecules Z(A beta 3)(12-58) and Z(A beta 3)(15-58) are highly promising for further engineering and future use as binding agents to monomeric A beta(1-40)

Keyword
amyloid, protein engineering, Alzheimer's disease, solid phase peptide synthesis, NMR spectroscopy
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-51261 (URN)10.1002/pro.511 (DOI)000284793800006 ()
Note
authorCount :9Available from: 2011-01-11 Created: 2011-01-10 Last updated: 2017-12-11Bibliographically approved
4. Specific binding of an engineered β-cyclodextrin dimer to the amyloid β peptide modulates the peptide aggregation process
Open this publication in new window or tab >>Specific binding of an engineered β-cyclodextrin dimer to the amyloid β peptide modulates the peptide aggregation process
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(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-60343 (URN)
Available from: 2011-08-15 Created: 2011-08-15 Last updated: 2011-08-19Bibliographically approved
5. pH dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid β peptide
Open this publication in new window or tab >>pH dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid β peptide
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(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-60345 (URN)
Available from: 2011-08-15 Created: 2011-08-15 Last updated: 2011-08-19Bibliographically approved

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