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The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 102021 (English)In: iScience, E-ISSN 2589-0042 , Vol. 24, no 8, article id 102852Article in journal (Refereed) Published
Abstract [en]

Substantial research efforts have gone into elucidating the role of protein misfolding and self-assembly in the onset and progression of Alzheimer’s disease (AD). Aggregation of the Amyloid-β (Aβ) peptide into insoluble fibrils is closely associated with AD. Here, we use biophysical techniques to study a peptide-based approach to target Aβ amyloid aggregation. A peptide construct, NCAM-PrP, consists of a largely hydrophobic signal sequence linked to a positively charged hexapeptide. The NCAM-PrP peptide inhibits Aβ amyloid formation by forming aggregates which are unavailable for further amyloid aggregation. In a membrane-mimetic environment, Aβ and NCAM-PrP form specific heterooligomeric complexes, which are of lower aggregation states compared to Aβ homooligomers. The Aβ:NCAM-PrP interaction appears to take place on different aggregation states depending on the absence or presence of a membrane-mimicking environment. These insights can be useful for the development of potential future therapeutic strategies targeting Aβ at several aggregation states.

Place, publisher, year, edition, pages
2021. Vol. 24, no 8, article id 102852
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:su:diva-198433DOI: 10.1016/j.isci.2021.102852ISI: 000686897200039PubMedID: 34381976OAI: oai:DiVA.org:su-198433DiVA, id: diva2:1609909
Available from: 2021-11-09 Created: 2021-11-09 Last updated: 2023-09-04Bibliographically approved
In thesis
1. Capturing transient peptide assemblies associated with Alzheimer's disease: Native mass spectrometry studies of amyloid-β oligomerization
Open this publication in new window or tab >>Capturing transient peptide assemblies associated with Alzheimer's disease: Native mass spectrometry studies of amyloid-β oligomerization
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Correct folding of proteins is essential for maintaining a functional living cell. Misfolding and aggregation of proteins, where non-native intermolecular interactions form large and highly ordered amyloid aggregates with low free energy, is hence associated with multiple diseases. One example is Alzheimer’s disease (AD) where the Amyloid-β (Aβ) peptide aggregates into amyloid fibrils, which deposit as neuritic plaques in the brains of AD patients. Nucleation of amyloid fibrils takes place via formation of smaller pre-nucleation clusters, so-called oligomers, which are considered to be especially toxic and are therefore potentially important in AD pathology. Detailed mechanistic molecular knowledge of Aβ aggregation is important for design of AD treatments that target these processes. The oligomeric species are however challenging to study experimentally due to their low abundance and high polydispersity.  

Aβ oligomers are in this thesis studied under controlled in vitro conditions using bottom-up biophysics. Highly pure recombinant Aβ peptides are studied, primarily using native ion-mobility mass spectrometry, to monitor the spontaneous formation of oligomers in aqueous solution. Mass spectrometry is capable of resolving individual oligomeric states, while ion mobility provides low-resolution structure information. This is complemented with other biophysical techniques, as well as theoretical modeling. The oligomers are also studied upon modulating intrinsic factors, such as peptide length and sequence, or extrinsic factors, such as the chemical environment. Interactions with two important biological interaction partners are studied: chaperone proteins and cell membranes.  

We show how Aβ oligomers assemble, and form extended structures which may be linked to continued growth into amyloid fibrils. We also show how different amyloid chaperone proteins interact with growing aggregates, which modifies and delays the aggregation process. These interactions are shown to depend on specific sequence-motifs in the chaperones and client peptides. Membrane-mimicking micelles are on the other hand able to stabilize globular compact forms of the Aβ oligomers and to inhibit the formation of extended structures which nucleate into amyloid fibrils. This may contribute to enrichment of toxic species in vivo. Interactions with membrane-mimicking systems are shown to be highly dependent on both the Aβ peptide isoform and the properties of the membrane environment, such as headgroup charges. It is also demonstrated how addition of a designed small peptide construct can inhibit formation of Aβ oligomers in the membrane environment. 

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2023. p. 74
Keywords
Protein aggregation, amyloid-β, neurodegeneration, Alzheimer’s disease, chaperones, DnaJ, biomembranes, native mass spectrometry
National Category
Biophysics Biochemistry and Molecular Biology Analytical Chemistry
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-212567 (URN)978-91-8014-130-7 (ISBN)978-91-8014-131-4 (ISBN)
Public defence
2023-01-27, Magnélisalen (AR-L208), Kemiska övningslaboratoriet, Svante Arrhenius väg 16B, Stockholm, 10:00 (English)
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Available from: 2023-01-02 Created: 2022-12-08 Last updated: 2022-12-21Bibliographically approved

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Król, SylwiaÖsterlund, NicklasVosough, FarazJarvet, JüriWärmländer, SebastianBarth, AndreasIlag, Leopold LunaGräslund, AstridMörman, Cecilia

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Król, SylwiaÖsterlund, NicklasVosough, FarazJarvet, JüriWärmländer, SebastianBarth, AndreasIlag, Leopold LunaGräslund, AstridMörman, Cecilia
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Department of Biochemistry and BiophysicsDepartment of Materials and Environmental Chemistry (MMK)
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