Mitigation of pathological tau abnormalities by the natural antioxidant uric acid: Comparison with DOT, a non-antibiotic oxytetracycline derivative

We aimed to model tau abnormalities in the early and advanced stages of Alzheimer’s disease and other tauopathies. By doing so, we wanted to evaluate molecules capable of preventing tau-mediated neurodegeneration. To achieve this, we established cultures of mouse cortical neurons in which hyperphosphorylated (but not aggregated) tau accumulates in a significant population of neurons following chronic exposure to redox-active iron from hemin (Hm), a breakdown product of hemoglobin. Using experimental conditions in which p-tau (AT8 immunosignal) accumulation occurs without concomitant neuronal loss, we found that the end-product of purine metabolism, uric acid (UA), but neither its immediate precursor xanthine nor its oxidized product allantoin prevents p-tau build-up. Imaging studies with the fluorogenic probe DHR-123 revealed that UA reduced p-tau load by inhibiting iron-dependent lipid peroxidation. Like UA, doxycycline (DOX) and a non-antibiotic derivative of oxytetracycline chemically referred to as 12a-deoxy-dedimethylamino-oxytetracycline (DOT) efficiently restrained p-tau accumulation and oxidative stress induced by Hm. Interestingly, UA and DOT (but not DOX) retained their capacity to prevent p-tau build-up when tau neurodegenerative changes were due to low-intensity excitotoxic-oxidative insults elicited by glutamate. Finally, using a thioflavin-T assay and 2N4R tau monomers to model tau aggregation at a later disease stage, we found that UA, DOT, and DOX restrained the formation of tau fibrils with the following order of potency: DOT>DOX>UA. Altogether, present results suggest that UA elevating agents and the non-antibiotic tetracycline DOT could have therapeutical utility to prevent tau-related abnormalities.