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Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model

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Abstract

Neurofibrillary tangles of the Tau protein and plaques of the amyloid β peptide are hallmarks of Alzheimer’s disease (AD), which is characterized by the conversion of monomeric proteins/peptides into misfolded β-sheet rich fibrils. Halting the fibrillation process and disrupting the existing aggregates are key challenges for AD drug development. Previously, we performed in vitro high-throughput screening for the identification of potent inhibitors of Tau aggregation using a proxy model, a highly aggregation-prone hexapeptide fragment 306VQIVYK311 (termed PHF6) derived from Tau. Here we have characterized a hit molecule from that screen as a modulator of Tau aggregation using in vitro, in silico, and in vivo techniques. This molecule, an anthraquinone derivative named Purpurin, inhibited ~ 50% of PHF6 fibrillization in vitro at equimolar concentration and disassembled pre-formed PHF6 fibrils. In silico studies showed that Purpurin interacted with key residues of PHF6, which are responsible for maintaining its β-sheets conformation. Isothermal titration calorimetry and surface plasmon resonance experiments with PHF6 and full-length Tau (FL-Tau), respectively, indicated that Purpurin interacted with PHF6 predominantly via hydrophobic contacts and displayed a dose-dependent complexation with FL-Tau. Purpurin was non-toxic when fed to Drosophila and it significantly ameliorated the AD-related neurotoxic symptoms of transgenic flies expressing WT-FL human Tau (hTau) plausibly by inhibiting Tau accumulation and reducing Tau phosphorylation. Purpurin also reduced hTau accumulation in cell culture overexpressing hTau. Importantly, Purpurin efficiently crossed an in vitro human blood–brain barrier model. Our findings suggest that Purpurin could be a potential lead molecule for AD therapeutics.

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Acknowledgements

This work was supported in part by the Alliance Family Foundation, and the Rosetrees Trust (to DS). This work was done in collaboration with the BLAVATNIK CENTER for Drug Discovery supported by the Blavatnik Family Foundation. GKV thanks TATA post-doctoral scholarship. Authors are grateful to the members of EG and DS research groups for fruitful discussions. We thank Donna Elyashiv Revivo for introduction and advice on fly work. Authors thank Dr. Vered Holdengreber for help with Electron Microscopy.

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Author notes

  1. Guru Krishnakumar Viswanathan and Dana Shwartz signify equal contribution to this work.

Authors and Affiliations

  1. Department of Molecular Microbiology and Biotechnology, School of Molecular Cell Biology and Biotechnology, Tel-Aviv University, 69978, Tel Aviv, Israel

    Guru Krishnakumar Viswanathan, Dana Shwartz, Yelena Losev, Ehud Gazit & Daniel Segal

  2. Ilse Katz Institute (IKI) for Nanoscale Science and Technology, Ben Gurion University of the Negev, 8410501, Beer Sheva, Israel

    Elad Arad & Raz Jelinek

  3. Department of Chemistry, Ben Gurion University of the Negev, 8410501, Beer Sheva, Israel

    Elad Arad & Raz Jelinek

  4. The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, 52621, Ramat Gan, Israel

    Chen Shemesh & Itzik Cooper

  5. Blavatnik Center for Drug Discovery, Tel-Aviv University, 69978, Tel Aviv, Israel

    Edward Pichinuk, Hamutal Engel, Avi Raveh & Ehud Gazit

  6. Interdisciplinary Center Herzliya, Herzliya, Israel

    Itzik Cooper

  7. Blood–Brain Barrier Laboratory (LBHE), Université d’Artois, Lens, France

    Fabien Gosselet

  8. The Interdisciplinary Sagol School of Neurosciences, Tel-Aviv University, 69978, Tel Aviv, Israel

    Daniel Segal

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  1. Guru Krishnakumar Viswanathan
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  12. Ehud Gazit
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  13. Daniel Segal
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Contributions

GKV and DS conceived and designed the project. GKV and DSh conducted the lab experiments. LL contributed to the development of cell model and western blots. EA and RJ performed ITC and SPR assays. GKV, EP, and AR executed the high throughput screening assay. HE performed molecular docking. FG established the in vitro BBB model. CS and IC performed the BBB permeability assay. GKV, DSh, EG and DS prepared the manuscript. All authors read and approved the manuscript.

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Correspondence to Daniel Segal.

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Viswanathan, G.K., Shwartz, D., Losev, Y. et al. Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model. Cell. Mol. Life Sci. 77, 2795–2813 (2020). https://doi.org/10.1007/s00018-019-03312-0

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  • DOI: https://doi.org/10.1007/s00018-019-03312-0

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