Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model
| العنوان: | Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model |
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| المؤلفون: | Hamutal Engel, Fabien Gosselet, Elad Arad, Guru KrishnaKumar Viswanathan, Itzik Cooper, Dana Shwartz, Chen Shemesh, Avi Raveh, Yelena Losev, Raz Jelinek, Daniel L. Segal, Edward Pichinuk, Ehud Gazit |
| المساهمون: | Tel Aviv University [Tel Aviv], Ben-Gurion University of the Negev (BGU), Sheba Medical Center, Blavatnik Center for Drug Discovery [Ramat Aviv, Israel], Interdisciplinary Center Herzliya (IDC), Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), Department of Molecular Microbiology and Biotechnology |
| المصدر: | Cellular and Molecular Life Sciences Cellular and Molecular Life Sciences, Springer Verlag, 2019, ⟨10.1007/s00018-019-03312-0⟩ |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Amyloid, Inhibitor, [SDV]Life Sciences [q-bio], In silico, Transgene, Tau protein, Anthraquinones, tau Proteins, Fibril, Animals, Genetically Modified, Aggregation, Protein Aggregates, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, In vivo, Animals, Humans, Phosphorylation, Surface plasmon resonance, Molecular Biology, Purpurin, 030304 developmental biology, Pharmacology, 0303 health sciences, Amyloid beta-Peptides, biology, PHF6 peptide, Chemistry, Isothermal titration calorimetry, Cell Biology, Peptide Fragments, In vitro, 3. Good health, Repressor Proteins, Disease Models, Animal, Drosophila melanogaster, Blood-Brain Barrier, biology.protein, Biophysics, Molecular Medicine, Protein Conformation, beta-Strand, Hydrophobic and Hydrophilic Interactions, Oligopeptides, 030217 neurology & neurosurgery |
| الوصف: | International audience; 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. |
| تدمد: | 1420-9071 1420-682X |
| DOI: | 10.1007/s00018-019-03312-0 |
| DOI: | 10.1007/s00018-019-03312-0⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd0427d33b2371643803bc263498a6f9 https://doi.org/10.1007/s00018-019-03312-0 |
| Rights: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....dd0427d33b2371643803bc263498a6f9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14209071 1420682X |
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| DOI: | 10.1007/s00018-019-03312-0 |