Doxycycline interferes with tau amyloid aggregation abolishing its associated neuronal toxicity

Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.11.18.388561v1?rss=1
Authors: Medina, L., Gonzalez Lizarraga, F., Dominguez Meijide, A., Ploper, D., Parrales, V., Sequeira, S., Cima Omorri, M. S., Zweckstetter, M., del Bel, E., Michel, P. P., Fleming Outeiro, T., Raisman-Vozari, R., Chehin, R. N., Socias, S. B.
Abstract:
Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts alpha-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the different isoforms of tau protein in a dose-dependent manner, remodeling the resultant species. Furthermore, doxycycline interacts with tau microtubule-binding domain preventing its aggregation. In a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.
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