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Designed Cell-Penetrating Peptide Inhibitors of Amyloid-beta Aggregation and Cytotoxicity
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.
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2020 (English)In: Cell Reports Physical Science, E-ISSN 2666-3864, Vol. 1, no 2, article id 100014Article in journal (Refereed) Published
Abstract [en]

Amyloid proteins and peptides are a major contributing factor to the development of various neurodegenerative disorders, including Alzheimer’s and prion diseases. Previously, a designed cell-penetrating peptide (CPP) comprising a hydrophobic signal sequence followed by a prion protein (PrP)-derived polycationic sequence (PrP23–28: KKRPKP) was shown to have potent anti-prion properties. Here, we extend this approach toward the amyloid-beta (Aβ) peptide amyloid formation, which is associated with Alzheimer’s disease. We characterized the interactions of the CPP with Aβ using complementary in vitro and in silico experiments. We report that the CPP stabilizes Aβ in a non-amyloid state and inhibits Aβ-induced neurotoxicity. Moreover, replacing PrP23–28 with a corresponding segment from Aβ results in a construct with similar CPP functionality and antagonism of Aβ aggregation and neurotoxicity. Our findings reveal a general underlying principle for inhibition of pathogenic protein aggregation that may facilitate the design of CPP-based therapeutics for amyloid diseases.

Place, publisher, year, edition, pages
2020. Vol. 1, no 2, article id 100014
Keywords [en]
aggregation, Alzheimer’s disease, amyloid-beta peptide, cell-penetrating peptides, drug design, neurodegeneration, oligomers, prion protein, protein engineering, signal sequence
National Category
Chemical Sciences
Research subject
Biophysics
Identifiers
URN: urn:nbn:se:su:diva-181494DOI: 10.1016/j.xcrp.2020.100014OAI: oai:DiVA.org:su-181494DiVA, id: diva2:1428688
Available from: 2020-05-06 Created: 2020-05-06 Last updated: 2022-07-27Bibliographically 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, CeciliaKról, SylwiaWärmländer, Sebastian K. T. S.Jarvet, JüriGräslund, Astrid

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