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Structure and dynamics of amyloid-beta oligomers
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0001-5856-3226
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer's disease (AD) is the most common cause of dementia, affects tens of millions of people all over the world and inflicts huge socioeconomic costs on the societies. AD is a neurodegenerative disease; it progresses over time and is highly debilitating at the advanced stages. Biochemical and genetic studies in the last decades have revealed that amyloid-beta (Aβ) peptides play underlying roles in the molecular pathology of AD. Aβ peptides are small, aggregation-prone polypeptides produced in the neural tissue. Soluble aggregates of Aβ peptides, known as Aβ oligomers are regarded as the major neurotoxic species in AD brain.

In this thesis, in vitro studies were performed on Aβ oligomers with a number of spectroscopy and biochemical methods. The main technique used in this thesis is infrared (IR) spectroscopy, a variety of vibrational spectroscopy methods. IR spectroscopy measures the absorption of IR radiation by the vibrational transitions of oscillating dipoles within chemical structures and provides structural information on chemical bonds and functional groups in molecules. The method can provide valuable data on the secondary structure of proteins and therefore is a powerful tool for studying protein self-assembly and aggregation.

Different samples of homogeneous and heterogeneous Aβ42 oligomers were prepared and studied with IR spectroscopy and biochemical methods to establish correlations between oligomers' physical properties (size and homogeneity) and IR parameters. Additionally, the effects of lithium and nickel ions on the formation of homogeneous Aβ42 oligomers were studied. Separately, isotope-edited IR spectroscopy was used to study the molecular structure of homogeneous and heterogeneous Aβ42 oligomers. The obtained data can be helpful to establish IR spectroscopy for characterization of Aβ oligomers, as well as studies on their dynamics and interactions with each other and other biomolecules or inorganic materials. Moreover, the findings in this thesis add to the available knowledge on the molecular structure of Aβ oligomers and help to develop relevant molecular models. Such information can be helpful for the development of diagnostics and therapeutic strategies for AD.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University , 2022. , p. 97
Keywords [en]
Alzheimer's disease, amyloid-beta peptide, Aβ oligomer, infrared spectroscopy, FTIR, protein aggregation, β-sheet, interaction, lithium, nickel
National Category
Biochemistry and Molecular Biology Structural Biology Neurosciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-210305ISBN: 978-91-8014-052-2 (print)ISBN: 978-91-8014-053-9 (electronic)OAI: oai:DiVA.org:su-210305DiVA, id: diva2:1702748
Public defence
2022-11-25, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16B and online via Zoom: https://stockholmuniversity.zoom.us/j/4563593316, Stockholm, 14:00 (English)
Opponent
Supervisors
Available from: 2022-11-01 Created: 2022-10-11 Last updated: 2022-11-01Bibliographically approved
List of papers
1. Characterization of Homogeneous and Heterogeneous Amyloid-beta 42 Oligomer Preparations with Biochemical Methods and Infrared Spectroscopy Reveals a Correlation between Infrared Spectrum and Oligomer Size
Open this publication in new window or tab >>Characterization of Homogeneous and Heterogeneous Amyloid-beta 42 Oligomer Preparations with Biochemical Methods and Infrared Spectroscopy Reveals a Correlation between Infrared Spectrum and Oligomer Size
2021 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 12, no 3, p. 473-488Article in journal (Refereed) Published
Abstract [en]

Soluble oligomers of the amyloid-β(1-42) (Aβ42) peptide, widely considered to be among the relevant neurotoxic species involved in Alzheimer’s disease, were characterized with a combination of biochemical and biophysical methods. Homogeneous and stable Aβ42 oligomers were prepared by treating monomeric solutions of the peptide with detergents. The prepared oligomeric solutions were analyzed with blue native and sodium dodecyl sulfate polyacrylamide gel electrophoresis, as well as with infrared (IR) spectroscopy. The IR spectra indicated a well-defined β-sheet structure of the prepared oligomers. We also found a relationship between the size/molecular weight of the Aβ42 oligomers and their IR spectra: The position of the main amide I′ band of the peptide backbone correlated with oligomer size, with larger oligomers being associated with lower wavenumbers. This relationship explained the time-dependent band shift observed in time-resolved IR studies of Aβ42 aggregation in the absence of detergents, during which the oligomer size increased. In addition, the bandwidth of the main IR band in the amide I′ region was found to become narrower with time in our time-resolved aggregation experiments, indicating a more homogeneous absorption of the β-sheets of the oligomers after several hours of aggregation. This is predominantly due to the consumption of smaller oligomers in the aggregation process.

Keywords
Amyloid-beta peptide, antiparallel beta-sheet, FTIR spectroscopy, infrared spectroscopy, oligomer
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-191785 (URN)10.1021/acschemneuro.0c00642 (DOI)000618157100010 ()33455165 (PubMedID)
Available from: 2021-04-27 Created: 2021-04-27 Last updated: 2023-08-28Bibliographically approved
2. Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation
Open this publication in new window or tab >>Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation
Show others...
2021 (English)In: Acta Biochimica Polonica, ISSN 0001-527X, E-ISSN 1734-154X, Vol. 68, no 2, p. 169-179Article in journal (Refereed) Published
Abstract [en]

Alzheimer’s disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has shown promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. The plaques contain also metal ions of e.g. Cu, Fe, and Zn, and such ions are known to interact with Aβ peptides and modulate their aggregation and toxicity. The interactions between Aβ peptides and Li+ions have however not been well investigated. Here, we use a range of biophysical techniques to characterize in vitro interactions between Aβ peptides and Li+ions. We show that Li+ions display weak and non-specific interactions with Aβ peptides, and have minor effects on Aβ aggregation. These results indicate that possible beneficial effects of Li on AD pathology are not likely caused by direct interactions between Aβ peptides and Li+ions.

Keywords
Alzheimer's disease, protein aggregation, metal-protein binding, neurodegeneration, pharmaceutics
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-196438 (URN)10.18388/abp.2020_5493 (DOI)000659435200003 ()33909969 (PubMedID)
Available from: 2021-09-08 Created: 2021-09-08 Last updated: 2022-10-11Bibliographically approved
3. Interactions of Ni(II) ions with the amyloid-beta (Aβ) peptide: effects on Aβ structure and aggregation
Open this publication in new window or tab >>Interactions of Ni(II) ions with the amyloid-beta (Aβ) peptide: effects on Aβ structure and aggregation
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-210542 (URN)
Note

Full list of authors: Elina Berntsson, Faraz Vosough, Teodor Svantesson, Jonathan Pansieri, Igor A. Iashchishyn, Lucija Ostojić, Xiaolin Dong, Suman Paul, Jüri Jarvet, Per M. Roos, Andreas Barth, Ludmilla Morozova-Roche, Astrid Gräslund, Sebastian K.T.S. Wärmländer

Available from: 2022-10-20 Created: 2022-10-20 Last updated: 2022-10-20
4. Distinct molecular structure of different Amyloid-β42 oligomers revealed by isotope-edited FTIR spectroscopy
Open this publication in new window or tab >>Distinct molecular structure of different Amyloid-β42 oligomers revealed by isotope-edited FTIR spectroscopy
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Distinct molecular structure of different Amyloid-β42 oligomers revealed by isotope-edited FTIR spectroscopy

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-210543 (URN)
Note

Full list of auhtors: Faraz Vosough and Andreas Barth. 

Available from: 2022-10-20 Created: 2022-10-20 Last updated: 2022-10-20

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