Long-term Nrf2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy

A prominent pathological feature of tauopathies, including Alzheimer’s disease, is a chronic microglial reactivity, which contributes to neuroinflammation and disease progression. Microglia, the innate immune cells of the brain, can be pharmacologically eliminated by inhibiting the colony stimulating factor 1 receptor (e.g. with PLX5622), which is essential for their survival and proliferation. Upon inhibitor withdrawal, microglia rapidly repopulate, replenishing the central nervous system niche with naïve cells. In recent years, microglia repopulation strategies have gained great interest as a means to reprogram dysfunctional microglia, while avoiding the detrimental effects of prolonged immune depletion. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglial remain poorly understood. Here, we investigate whether repopulated microglia after PLX5622 treatment sustains their beneficial effects over time in an AAV-hTauP301L induced model. Additionally, we assessed whether activating the cytoprotective nuclear factor erythroid 2 p45–related factor 2 (Nrf2) during microglial repopulation enhanced and prolonged the therapeutic outcomes. While microglial repopulation alone failed to maintain its neuroprotection in the long-term, when combined with an Nrf2 inducer, it improved cognitive deficits, reverted hippocampal neuronal loss and restored microglial phenotypes and mitochondrial energetics homeostasis, in our tauopathy-induced model. These results highlight the importance of shaping the fate of self-renewed microglia and propose Nrf2-mediated microglia repopulation as a potential pharmacological strategy for the treatment of tauopathies.