Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience II

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. Droplet-based single nuclear RNA sequencing of mouse hippocampus of WT, cgas+/- and cgas-/- with and without the presence of P301S Tau.