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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
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0001-5784-7673
Number of Authors: 22021 (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.

Place, publisher, year, edition, pages
2021. Vol. 12, no 3, p. 473-488
Keywords [en]
Amyloid-beta peptide, antiparallel beta-sheet, FTIR spectroscopy, infrared spectroscopy, oligomer
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-191785DOI: 10.1021/acschemneuro.0c00642ISI: 000618157100010PubMedID: 33455165OAI: oai:DiVA.org:su-191785DiVA, id: diva2:1547615
Available from: 2021-04-27 Created: 2021-04-27 Last updated: 2023-08-28Bibliographically approved
In thesis
1. Structure and dynamics of amyloid-beta oligomers
Open this publication in new window or tab >>Structure and dynamics of amyloid-beta oligomers
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
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:nbn:se:su:diva-210305 (URN)978-91-8014-052-2 (ISBN)978-91-8014-053-9 (ISBN)
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)
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Available from: 2022-11-01 Created: 2022-10-11 Last updated: 2022-11-01Bibliographically approved

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Vosough, FarazBarth, Andreas

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