Timing of microglial ablation determines protection from tau-mediated neurodegeneration and cognitive decline

Tauopathies comprise a diverse group of neurodegenerative diseases characterized by intracellular aggregation of the microtubule-associated protein tau, neuroinflammation, and neuronal loss. Since tau pathology shows the strongest correlation with cognitive decline in Alzheimer’s disease, understanding how microglia contribute to tau-mediated neurodegeneration remains a critical question. Here, we validated a tauopathy mouse model that progressively recapitulates key pathological features of tauopathy. Bilateral hippocampal injection of AAV-hTau P301L (AAV-hTau) resulted in widespread tau accumulation, early and sustained gliosis, complement component 1q (C1q) deposition, progressive reduction of hippocampal layer thickness and cognitive deficits. Notably, we observed marked activation of Cluster of Differentiation 68 (CD68 + ) microglia and the emergence of Complement 3 (C3 + ) reactive astrocytes, which developed in parallel over time. To dissect the role of microglia in tau-driven pathology, we depleted them at different stages using the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. Microglial ablation conferred significant neuroprotection, with early depletion effectively mitigating cognitive decline and structural changes in hippocampal layers supporting an important role for microglial activation in tauopathy progression.Neuroprotection may result from decreased levels of insoluble p-tau oligomers, partial blockade of C3 + astrocyte induction and attenuation of microglial reactivity. Overall, our results support the potential of microglia-directed interventions as a promising therapeutic avenue for mitigating disease progression in tauopathies.