Doxycycline interacts with tau forming different oligomeric species: expanding the target for pautative repurposing of this drug

MEDINA, L.; SEQUEIRA, S.; VERA, C.; GONZALEZ LIZARRAGA, F; BARBOSA, L.; PAPY-GARCIA, D; RAISMAN- VOZARI, R; CHEHÍN, R.

Congreso; 11th FENS Forum of Neuroscience; 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 protein, whose malfunction and deregulation leads to tauopathies such as Alzheimer´s disease.Alzheimer´s disease (AD) is a neurodegenerative disease histologically characterized by the extracellular accumulation of senile plaques consisting of amyloid-β protein and intracellular amyloid aggregates. These intracellular aggregates appear as paired helical filaments (PHFs) or straight filaments which associate into the higher order structures of neurofibrillary tangles (NFTs). The later are made of abnormally phosphorylated Tau and its formation in the central nervous system has been proposed to play a central role in the development and evolution of AD.