Doxycycline interacts with tau protein forming less toxic species: a biophysical approach

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

La Plata

Congreso; XLVII Reunión Anual de la Sociedad Argentina de Biofísica; 2018

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 are involved in neurodegeneration in Alzheimer's disease. Using fluorescence and infrared spectroscopy we analyzed tau conformational changes in order to understand the molecular events leading to aggregation. According with our results, heparin can induce tau aggregation with a classical sigmoidal behavior 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 affect the 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.Our results strongly suggest that doxycycline could be a selective inhibitor of the main neurotoxic oligomeric species.