Doxycycline induces a less toxic tau aggregated strain: a novel target for repurposing this antibiotic as neuroprotector.

VALERIA PARRALES MACIAS; RITA RAISMAN-VOZARI; LUCIANA MEDINA; NICOLAS BIZAT; ROSANA NIEVES CHEHIN; MARIA FLORENCIA GONZALEZ LIZARRAGA; LEANDRO RAMOS SOUZA BARBOSA

Lima

Encuentro; Revisiting the Central Dogma of Molecular Biology at the Single-Molecule Level; 2019

Biophysical Society

Tauopathies are a diverse group of neurodegenerative diseases characterized by clinical heterogeneity and progressive deposition of tau protein aggregates in characteristic brain regions. Tau can adopt multiple and stable propagating conformers in vitro called ?strains? and nowadays, some evidence supports the idea that the variation in amyloid aggregation results in different tauopathies in living systems. Based on the ability of doxycycline to reshape oligomeric species of alpha-synuclein, we explored whether doxycycline is able to interact with tau species by modifying its conformation and intervening in its toxicity. To do this, we used the heparin-induced tau fibrillation model and according to electron microscopy techniques, our results show that doxycycline interacts with aggregated species inducing the formation of morphologically differentiated species. These novel species display different β-sheet structural arrangement according with FTIR studies and have different protease digestion pattern. These data suggest that aggregates obtained in the presence and in the absence of doxycycline would correspond to different strains. In addition to amyloidaggregation, abnormal phosphorylation is also a characteristic of toxicity in aggregated species of tau. For this reason we also studied whether doxycycline was able to induce changes in the phosphorylation patterns of the protein induced by GSK3-β. According to our results, the antibiotic may not affect the phosphorylation pattern, as doxycycline does not interfere on the GSK3-β activity. To move this concept to an in vivo model, we used a C. elegans tauopathy model and our data demonstrate that doxycycline could revert the low mobility phenotype induced by the over expression of human tau.The results presented herein suggest that the presence of doxycycline induces a novel and less toxic tau aggregation strain, but do not interfere with its pathological phosphorylation. Therefore, the aggregation process could be the primary event in the toxicity cascade.