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

MEDINA, LUCIANA; VERA, CECILIA ; GONZÁLEZ LIZARRAGA, MARÍA FLORENCIA; SEQUEIRA, SABRINA; PARRALES, V; BIZAT, N; RAMOS SOUZA BARBOSA, LEANDRO; RAISMAN-VOZARI, RITA; CHEHÍN, ROSANA NIEVES

La Plata

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

Sociedad Argentina de Biofísica

Amyloid aggregation of specific proteins seems to be the common biological eventinvolved in neuronal death in different neurodegenerative diseases. Interferingwith 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 fillthe gap between the increasing incidence of neurodegenerative diseases and thelong-term assessment of classical drug discovery technologies.Doxycycline, a second generation tetracycline, prevents neurodegeneration inanimal models. We have been able to demonstrate the ability of this antibiotic toreshape alpha-synuclein oligomers into off-pathway non-toxic species, unable todestabilize biological membranes and thus, cell viability. Herein, we extendedthese studies to Tau, whose aggregation and phosphorylation are involved inneurodegeneration in Alzheimer's disease.Using fluorescence, infrared and SAXS spectroscopy we analyzed tauconformational changes in order to understand the molecular events leading toaggregation. According with our results, heparin can induce tau aggregation with aclassical sigmoidal behavior and the presence of doxycycline strongly inhibits theamyloid fibrils formation, although oligomeric species are still formed. Doxycyclinedoes not inhibit the GSK3-beta activity, suggesting that the antibiotic may notaffect the phosphorylation pattern. Since results suggest that doxycycline mayform different tau oligomeric species, we are evaluating its effects in a C. elegansmodel expressing human tau and in SH-5YSY cells. We have also testeddoxycycline effect in other protein aggregation models without the effectsobtained with alpha-synuclein and Tau.Our results strongly suggest that doxycycline could be a selective inhibitor of themain neurotoxic oligomeric species.