Lamivudine ameliorates neuropathology in 5×FAD mice via coordinated inhibition of the cGAS-STING pathway with enhancement of mitophagy.

Alzheimer's disease is a neurodegenerative disorder for which there is currently no effective treatment available. Epidemiological and clinical evidence suggests that lamivudine, a nucleoside reverse transcriptase inhibitor, is associated with a reduced risk of Alzheimer's disease and shows potential in alleviating neuroinflammation. This study therefore aims to employ AD mouse models to further investigate the molecular mechanisms by which lamivudine ameliorates AD-related phenotypes. In this study, we showed that lamivudine administration inhibited cGAS-STING activation and attenuated mitochondrial damage in the 5 ×FAD mouse model, as supported by improved mitochondrial morphology and enhanced mitophagy. These changes were associated with improved spatial memory, alongside reduced neuronal apoptosis and synaptic loss. Our findings underscore the neuroprotective potential of lamivudine in AD via coordinated preservation of mitochondrial integrity and suppression of innate immune signaling, suggesting its promise for clinical translation in neurodegenerative disorders.