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Transthyretin Interferes with Aβ Amyloid Formation by Redirecting Oligomeric Nuclei into Non-Amyloid Aggregates
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 17, p. 2722-2733Article in journal (Refereed) Published
Abstract [en]

The pathological Aβ aggregates associated with Alzheimer's disease follow a nucleation-dependent path of formation. A nucleus represents an oligomeric assembly of Aβ peptides that acts as a template for subsequent incorporation of monomers to form a fibrillar structure. Nuclei can form de novo or via surface-catalyzed secondary nucleation, and the combined rates of elongation and nucleation control the overall rate of fibril formation. Transthyretin (TTR) obstructs Aβ fibril formation in favor of alternative non-fibrillar assemblies, but the mechanism behind this activity is not fully understood. This study shows that TTR does not significantly disturb fibril elongation; rather, it effectively interferes with the formation of oligomeric nuclei. We demonstrate that this interference can be modulated by altering the relative contribution of elongation and nucleation, and we show how TTR's effects can range from being essentially ineffective to almost complete inhibition of fibril formation without changing the concentration of TTR or monomeric Aβ.

Place, publisher, year, edition, pages
Elsevier, 2018. Vol. 430, no 17, p. 2722-2733
Keywords [en]
Aβ, Surface Plasmon Resonance, Thioflavin-T, amyloid, transthyretin
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-148930DOI: 10.1016/j.jmb.2018.06.005ISI: 000441645300013PubMedID: 29890120OAI: oai:DiVA.org:umu-148930DiVA, id: diva2:1218104
Funder
The Dementia Association - The National Association for the Rights of the DementedThe Kempe FoundationsSwedish Research CouncilMagnus Bergvall FoundationTorsten Söderbergs stiftelseAvailable from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-09-05Bibliographically approved

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Nilsson, LinaBrännström, KristofferIakovleva, IrinaSandblad, LindaGharibyan, Anna L.

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Nilsson, LinaPamrén, AnnelieIslam, TohidulBrännström, KristofferIakovleva, IrinaSandblad, LindaGharibyan, Anna L.Olofsson, Anders
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Department of Medical Biochemistry and BiophysicsDepartment of Molecular Biology (Faculty of Medicine)
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