Biophysical Society Thematic Meeting| Lima 2019

Revisiting the Central Dogma of Molecular Biology at the Single-Molecule Level

Poster Abstracts

35-POS Board 35 DOXYCYCLINE INDUCES A LESS TOXIC TAU AGGREGATED STRAIN: A NOVEL TARGET FOR REPURPOSING THIS ANTIBIOTIC AS NEUROPROTECTOR. Luciana Medina 1,2 ; Claudia C Vera 4 ; Sabrina Sequeira 1 ; Maria Florencia Gonzalez Lizarraga 1 ; Valeria Parrales 2 ; Nicolas Bizat 3 ; Rita Raisman-Vozari 2 ; Rosana N Chehin 1 ; 1 Instituto de Investigación en Medicina Molecular Aplicada (IMMCA), CONICET-UNT- SIPROSA, San Miguel de Tucuman, Argentina 2 Institute for Brain and Spinal Cord (ICM), Experimental Therapeutics of Parkinson’s disease, Paris, France 3 Institute for Brain and Spinal Cord (ICM), Alzheimer’s disease and prion diseases, Paris, France 4 Instituto de Bionanotecnología del NOA (INBIONATEC) , CONICET-UNSE, Santiago del Estero, Argentina Objective: Tauopathies are a diverse group of neurodegenerative diseases characterized by a progressive deposition of abnormally phosphorylated tau protein aggregates, in characteristic brain regions. Tau can adopt multiple propagating conformers in vitro, nowadays called “strains”.Based on doxycycline's neuroprotective effect reported for a Parkinson disease model, we explored whether doxycycline is able to interact with tau.For this reason, we studied if doxycycline was able to induce changes in tau amyloid aggregation process and phosphorylation patterns. The neuroprotective effect of doxycycline was evaluated on an in vivo model of tauopathy.Methods: For the in vitro assays, we used the heparin-induced tau fibrillation model; to perform Transmission Electron Microscopy (TEM), Thioflavin T fluorescence spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), and protease digestion of aggregated tau species; in the presence and in the absence of doxycycline. We performed in vitro phosphorylation of tau using Glycogen synthase kinase-3 beta (GSK3-beta). And to evaluate doxycycline neuroprotective effect we used a C. elegans tauopathy model.Results: Our results show that doxycycline interacts with tau inducing the formation of morphologically differentiated species, observed by TEM. These novel species display different beta-sheet structural arrangement according to FTIR studies and have different protease digestion pattern.Doxycycline does not interfere on the GSK3 beta activity, as tau phosphorylation pattern remains the same.Our data demonstrate that doxycycline could revert the low mobility phenotype induced by the over expression of human tau by the nematode C. elegans.Conclusions: Our results reveal that doxycycline shows a neuroprotective effect over a C. elegans tauopathy model, and the mechanism of toxicity reduction would be the interference over tau amyloid fibrillogenesis. The presence of doxycycline might induce a novel and less toxic tau aggregation strain, making this antibiotic a good candidate to be repurposed as neuroprotector for tauopathies.

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