Tau-activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience

Pathological hallmarks of Alzheimer disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of cGAS in tauopathy mice diminished microglial IFN-I response, preserved synapse integrity and plasticity, and protected against cognitive impairment without affecting the pathogenic tau load.  cGAS ablation enhanced, while activation of IFN-I downregulated, neuronal MEF2C expression network linked with cognitive resilience in AD. Pharmacological inhibition of cGAS in tauopathy mice enhanced neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity, and memory, supporting the therapeutic potential of targeting cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.