Pathogenic tau activates cGAS in microglia, in part by triggering the leakage of mtDNA into the cytosol (Fig. 3). Microglial cGAS-STING activation leads to the secretion of IFN-inducible cytokines, such as CXCL10 and CCL5, and upregulation of ISGs, such as Stat1, Trim30a, and Ddx60. Genetic deletion of Cgas in tauopathy mice mitigated tauopathy-induced microglial IFN-I and protected against synapse loss, synaptic plasticity, and cognitive deficits. Here, MAPT is linked to tauopathy.