Impact of chronic doxycycline treatment in a mouse model of tauopathy

Tauopathies are neurodegenerative disorders characterized by the accumulation of hyperphosphorylated tau, leading to synaptic dysfunction, neuroinflammation, and both cognitive and motor impairments. Doxycycline (Doxy), a tetracycline antibiotic commonly used to treat bacterial infections and skin conditions, has also shown some anti-inflammatory and anti-aggregation properties in preclinical models of brain diseases. In this study, we sought to investigate the effects of chronic Doxy treatment in htau transgenic mice, which express human tau isoforms on a Mapt −/− background. Wild-type (WT) and htau mice received a Doxy-supplemented or normal diet from 6 to 9 months of age, after phenotypic onset. Behavioral analyses were performed, and brain nuclei were analyzed to assess inflammatory markers, glial activation, and pathological tau phosphorylation. Aged htau mice displayed impaired motor performance, memory deficits, delayed olfactory detection, and reduced striatal IL-10 levels, along with elevated tau phosphorylation at S396 relative to WT controls. Chronic Doxy treatment partially rescued motor and olfactory deficits. In the striatum, Doxy treatment restored IL-10 and GFAP levels, whereas no significant effects were observed in the olfactory bulb. Moreover, most Doxy-treated htau mice showed a reduction in striatal phospho-tau content. Overall, this study suggests that chronic Doxy treatment may partially attenuate behavioral deficits and modulate striatal neuroinflammation, providing new perspectives for the potential of repurposed tetracyclines as candidate therapeutic agents, primarily through immunomodulatory mechanisms.