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

Autor: 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
Přispěvatelé: 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
Rok vydání: 2019
Předmět:
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
Zdroj: Cellular and Molecular Life Sciences
Cellular and Molecular Life Sciences, Springer Verlag, 2019, ⟨10.1007/s00018-019-03312-0⟩
ISSN: 1420-9071
1420-682X
DOI: 10.1007/s00018-019-03312-0
Popis: 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.
Databáze: OpenAIRE
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