The reverse transcriptase inhibitor 3TC modulates hippocampal transcriptome signatures of inflammation in tauopathy model mice

Reducing neuroinflammation, a main hallmark of brain aging and neurodegenerative diseases, is a promising strategy for improving cognitive function in these settings. The nucleoside reverse transcriptase inhibitor 3TC (Lamivudine) has been reported to improve cognitive function in old wild-type mice and in multiple mouse models of neurodegenerative disease, but the underlying mechanisms have not been comprehensively investigated. In the current study, we used transcriptomics to broadly characterize the effects of long-term supplementation with a human-equivalent therapeutic dose of 3TC on the hippocampal transcriptome in male and female rTg4510 mice (a commonly studied model of tauopathy-associated neurodegeneration). We found that tauopathy increased hippocampal transcriptomic signatures of neuroinflammation/immune activation, but 3TC treatment reversed many of these transcriptome changes. We also found that 3TC mitigated tauopathy-associated activation of several key transcription factors that contribute to neuroinflammation and immune activation, and several of these changes were correlated with improved recognition memory performance.Our findings suggest that 3TC exerts beneficial effects on the hippocampus in the context of tauopathy by modulating pathways associated with inflammation and immune response.