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Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation-inert complex
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0003-4464-1769
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2020 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 295, no 21, p. 7224-7234Article in journal (Refereed) Published
Abstract [en]

A detailed understanding of the molecular pathways for amyloid-β (Aβ) peptide aggregation from monomers into amyloid fibrils, a hallmark of Alzheimer’s disease, is crucial for the development of diagnostic and therapeutic strategies. We investigate the molecular details of peptide fibrillization in vitro by perturbing this process through addition of differently charged metal ions. Here, we used a monovalent probe, the silver ion, that, similarly to divalent metal ions, binds to monomeric Aβ peptide and efficiently modulates Aβ fibrillization. On the basis of our findings, combined with our previous results on divalent zinc ions, we propose a model that links the microscopic metal ion binding to Aβ monomers to its macroscopic impact on the peptide self-assembly observed in bulk experiments. We found that sub-stoichiometric concentrations of the investigated metal ions bind specifically to the N-terminal region of Aβ, forming a dynamic, partially compact complex. The metal ion bound state appears to be incapable of aggregation, effectively reducing the available monomeric Aβ pool for incorporation into fibrils. This is especially reflected in a decreased fibril-end elongation rate. However, since the bound state is significantly less stable than the amyloid state, Aβ peptides are only transiently redirected from fibril formation and eventually almost all Aβ monomers are integrated into fibrils. Taken together, these findings unravel the mechanistic consequences of delaying Aβ aggregation via weak metal ion binding, quantitatively linking the contributions of specific interactions of metal ions with monomeric Aβ to their effects on bulk aggregation.

Place, publisher, year, edition, pages
2020. Vol. 295, no 21, p. 7224-7234
Keywords [en]
silver, monovalent ion, amyloid, neurodegeneration, zinc, protein aggregation, Alzheimer disease, metal, metal ion-protein interaction, nuclear magnetic resonance (NMR), amyloid-beta (AB)
National Category
Chemical Sciences
Research subject
Biophysics
Identifiers
URN: urn:nbn:se:su:diva-181490DOI: 10.1074/jbc.RA120.012738ISI: 000537733500005OAI: oai:DiVA.org:su-181490DiVA, id: diva2:1428682
Available from: 2020-05-06 Created: 2020-05-06 Last updated: 2022-03-23Bibliographically approved
In thesis
1. Self-assembly of amyloid-β peptides in the presence of metal ions and interacting molecules – a detour of amyloid building blocks
Open this publication in new window or tab >>Self-assembly of amyloid-β peptides in the presence of metal ions and interacting molecules – a detour of amyloid building blocks
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Misfolding of proteins into amyloid structures is implicated as a pathological feature in several neurodegenerative diseases and the molecular causes are still unclear. One typical characteristic of Alzheimer’s disease is self-assembly and accumulation of soluble amyloid-β (Aβ) peptides into insoluble fibrils and plaques. One way to provide fundamental knowledge about the underlying fibrillization processes is to perturb the aggregation by varying the experimental conditions. Two main aspects are included in this thesis work: interactions with the Aβ peptide, and modulation of the Aβ peptide aggregation kinetics. The interplay between the Aβ peptide and three different types of aggregation modulators was studied mainly in vitro by biophysical techniques such as NMR, circular dichroism, and fluorescence spectroscopy.

Metal ions, such as Ag(I), Cu(II), Hg(II), and Zn(II), at sub-stoichiometric concentrations with specific binding to monomeric Aβ peptides modulate and attenuate the Aβ self-assembly process. The bound (metal:Aβ) state removes Aβ monomers from the monomeric pool of amyloid building blocks used for fibril formation. In contrast, designed peptide constructs with cell-penetrating properties do not interact with monomeric Aβ, but exhibit an inhibitory effect on the Aβ oligomerization and fibrillization in vitro and in cells, via interactions with multimeric Aβ structures. The designed peptide constructs rescue Aβ-induced neurotoxicity and target both intracellular and extracellular Aβ. Full-length and native Tau protein, another protein implicated in Alzheimer’s disease, prevents the Aβ peptide fibrillization. The Aβ fibrillization process is not prevented by Tau interactions with the Aβ monomeric species, but rather with fibrils and oligomeric species of Aβ.

Here we showed that the Aβ peptide interacts with various metal ions and molecules, both at the monomeric stage and as larger assemblies, with resulting perturbation of the Aβ aggregation kinetics. The interactions and aggregation modulators can be used to learn more about the underlying fibrillization processes and for the development of potential therapeutic strategies.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2020. p. 77
Keywords
biophysics, Alzheimer’s disease, protein aggregation, amyloid formation, amyloid-β peptide, aggregation kinetics, interactions, metal ions, designed peptide constructs, Tau protein, NMR, circular dichroism, fluorescence spectroscopy
National Category
Chemical Sciences
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-181495 (URN)978-91-7911-188-5 (ISBN)978-91-7911-189-2 (ISBN)
Public defence
2020-09-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
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Available from: 2020-06-09 Created: 2020-05-15 Last updated: 2022-02-26Bibliographically approved

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Wallin, CeciliaJarvet, JüriWärmländer, SebastianDanielsson, JensGräslund, Astrid

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