Doxycycline interacts and reshapes tau oligomeric species diminishing their toxicity: expanding the target for putative repurposing of this old drug.

SABRINA SEQUEIRA ; LEANDRO RAMOS SOUZA BARBOSA; ROSANA NIEVES CHEHIN; CLAUDIA CECILIA VERA; DULCE PAPY-GARCIA; LUCIANA MEDINA; MARIA FLORENCIA GONZALEZ LIZARRAGA; RITA RAISMAN-VOZARI

Berlín

Congreso; 11th FENS Forum of Neuroscience; 2018

?Doxycycline interacts and reshapes tau oligomeric species diminishing their toxicity: expanding the target for putative repurposing of this old drug?.Amyloid aggregation of specific proteins seems to be the common biological event involved in neuronal death in different neurodegenerative diseases. Interfering with this abnormal aggregation could slow down or stop neuronal death. However, despite the huge effort invested,traditional drug discovery strategies have fallen. The exploration of new uses for approved drugs provides a useful alternative to fill the gap between the increasing incidence of neurodegenerative diseases and the long-term assessment of classical drug discovery technologies.Doxycycline, a second generation tetracycline, prevents neurodegeneration in animal models. We have been able to demonstrate the ability of this antibiotic to reshape alpha-synuclein oligomers into off-pathway non-toxic species, unable to destabilize biological membranes and thus, cell viability. Herein, we extended these studies to Tau, whose aggregation and phosphorylation areinvolved in neurodegeneration in Alzheimer's disease. According with our results, heparin can induce tau aggregation with a classical sigmoidal behaviour and the presence of doxycycline strongly inhibits the amyloid fibrils formation, although oligomeric species are still formed.Doxycycline does not inhibit the GSK3-beta activity, suggesting that the antibiotic may not affectthe phosphorylation pattern. Since results suggest that doxycycline may form different tau oligomeric species, we are evaluating its effects in a C. elegans model expressing human tau and in SH-5YSY cells. We have also tested doxycycline effect in other protein aggregation models without the effects obtained with alpha-synuclein and Tau.Our results strongly suggest that doxycycline could be a selective inhibitor of the main neurotoxic oligomeric species.