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Multivalent interacting glycodendrimer to prevent amyloid-peptide fibril formation induced by Cu(II): A multidisciplinary approach

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Abstract

Amyloid peptide fibrillogenesis induced by Cu(II) ions is a key event in the pathogenesis of Alzheimer’s disease. Dendrimers have been found to be active in preventing fibril formation. Therefore, they hold promise for the treatment of Alzheimer’s disease. In this study, the fibrillation mechanism of amyloid peptide Aβ 1-40 was studied by adding Cu(II) in the absence and presence of 4th generation poly(propyleneimine) glycodendrimer functionalized with sulfate groups, using dynamic light scattering (DLS), circular dichroism (CD), fluorescence, electron paramagnetic resonance (EPR) and molecular modeling (MD). The glycodendrimer was non-toxic to mHippoE-18 embryonic mouse hippocampal cells, selected as a nerve cell model, and decreased the toxicity of peptide aggregates formed after the addition of Cu(II). The binary systems of Cu(II)–glycodendrimer, Cu(II)–peptide, and glycodendrimer–peptide were first characterized. At the lowest Cu(II)/glycodendrimer molar ratios, Cu(II) was complexed by the internal-dendrimer nitrogen sites. After saturation of these sites, Cu(II) binding with sulfate groups occurred. Stable Cu(II)–peptide complexes formed within 5 min and were responsible for a transition from an α helix to a β-sheet conformation of Aβ 1-40. Glycodendrimer–peptide interactions provoked the stabilization of the α-helix, as demonstrated in the absence of Cu(II) by the Thioflavin T assay, and in the presence of Cu(II) by CD, EPR, and MD. Formation of fibrils is differentially modulated by glycodendrimer and Cu(II) concentrations for a fixed amount of Aβ 1-40. Therefore, this multidisciplinary study facilitated the recognition of optimal experimental conditions that allow the glycodendrimer to avoid the fibril formation induced by Cu(II).

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Acknowledgements

We wish to thank our students: Pawel Piatek and Agnieszka Karenko for their assistance with the collection of a part of the data. Authors also thank Mrs. Christiane Effenberg for synthesizing the glycodendirmer, Dr. Hartmut Komber for NMR measurements and Dr. Susanne Boye for AF4 measurements.

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Authors and Affiliations

  1. Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236, Lodz, Poland

    Anna Janaszewska, Barbara Klajnert-Maculewicz, Monika Marcinkowska & Maria Francesca Ottaviani

  2. Department of Biophysics of Environmental Pollution, Faculty of Biology and Environmental Protection, University of Lodz, 90-236, Lodz, Poland

    Piotr Duchnowicz

  3. Department Bioactive and Responsive Polymers, Leibniz Institute of Polymer Research, 01069, Dresden, Germany

    Dietmar Appelhans

  4. SUPSI-DTI IDSIA- Dalle Molle Institute for Artificial Intelligence, CH-6928, Manno, Switzerland

    Gianvito Grasso, Marco A. Deriu & Andrea Danani

  5. Department of Pure and Applied Sciences, University of Urbino, 61029, Urbino, Italy

    Michela Cangiotti & Maria Francesca Ottaviani

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  1. Anna Janaszewska
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  2. Barbara Klajnert-Maculewicz
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  3. Monika Marcinkowska
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  4. Piotr Duchnowicz
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  6. Gianvito Grasso
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  8. Andrea Danani
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  9. Michela Cangiotti
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  10. Maria Francesca Ottaviani
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Corresponding authors

Correspondence to Barbara Klajnert-Maculewicz, Andrea Danani or Maria Francesca Ottaviani.

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Multivalent interacting glycodendrimer to prevent amyloid-peptide fibril formation induced by Cu(II): A multidisciplinary approach

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Janaszewska, A., Klajnert-Maculewicz, B., Marcinkowska, M. et al. Multivalent interacting glycodendrimer to prevent amyloid-peptide fibril formation induced by Cu(II): A multidisciplinary approach. Nano Res. 11, 1204–1226 (2018). https://doi.org/10.1007/s12274-017-1734-9

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  • DOI: https://doi.org/10.1007/s12274-017-1734-9

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