**Background:** Alzheimer's disease (AD) is characterized by a long preclinical phase where amyloid-β plaques and tau aggregates accumulate before cognitive decline manifests, suggesting a period of cognitive resilience. Innate immune responses, particularly antiviral pathways, are implicated in the transition to symptomatic disease. The cyclic GMP-AMP synthase (cGAS)-STING pathway, a major antiviral DNA sensor, drives type I interferon (IFN-I) activation in neurodegenerative diseases, but its role in tau-mediated cognitive decline was unknown. The myocyte enhancer factor 2c (MEF2C) is a transcription factor linked to cognitive resilience in AD brains.
**Methods:** The authors used P301S tau transgenic mice crossed with Cgas-/- mice to generate cohorts with 0, 1, or 2 functional copies of Cgas. They performed bulk RNA-seq, single-nuclei RNA sequencing (snRNA-seq) of 221,150 hippocampal nuclei, behavioral testing (Morris water maze), electrophysiology (theta burst stimulation-induced LTP), and immunofluorescence. In vitro studies used primary mouse microglia, BV2 microglial cells, and human iPSC-derived microglia (hMGs) treated with tau fibrils. Mitochondrial DNA (mtDNA) leakage was assessed by digitonin-based cytosolic fractionation and qPCR. Pharmacological inhibition used the brain-penetrant cGAS inhibitor TDI-6570 (IC50 = 1.64 × 10^-6 M) administered in chow diet (150 mg/kg) for 3 months. STING agonist DMXAA (12.5 mg/kg, 5 injections over 12 days) was used in wild-type and Ifnar1-/- mice.
**Key Results:** Tau fibril treatment of primary microglia induced TBK1 phosphorylation and IFN-I cytokine expression (IFNβ, CXCL10, CCL5), which was abolished in Cgas-/- microglia. Tau localized to mitochondria and lysosomes by electron microscopy and triggered mtDNA release into the cytosol. Depletion of mtDNA with dideoxycytidine or ethidium bromide reduced tau-induced IFNβ responses in a dose-dependent manner. In P301S mice, snRNA-seq revealed that Cgas was expressed predominantly in microglia, and Cgas deletion suppressed IFN-I response genes (Trim30a, Stat1, Ddx60, Rnf213, Parp14) without affecting homeostatic or disease-associated microglial (DAM) gene programs. Despite no change in tau aggregate load (MC1 staining), Cgas deletion rescued spatial learning and memory in the Morris water maze (P301S Cgas-/- mice spent more time in the target quadrant vs P301S Cgas+/+ mice), restored late-phase LTP (60 min post-TBS), and rescued PSD-95 synaptic density in CA1. snRNA-seq of excitatory and inhibitory neurons showed that Cgas deletion upregulated Mef2c and its target genes (e.g., Ncald, Rasgef1b, Igsf3, R3hdm2), with significant overlap with cognitive resilience genes from human AD brains. MEF2C target gene enrichment was specific (not seen for MEF2A, FOSL2, JUNB, or activity-regulated genes). In human AD brain snRNA-seq data (70 individuals), microglial IFN-inducible gene expression (RNF213, IRF3) inversely correlated with neuronal MEF2C expression. STING agonist DMXAA in wild-type mice suppressed neuronal Mef2c and its targets, an effect absent in Ifnar1-/- mice. Pharmacological cGAS inhibition with TDI-6570 for 3 months in P301S mice rescued novel object recognition, increased LTP magnitude, and restored PSD-95 and vGAT synaptic densities, with snRNA-seq confirming upregulation of MEF2C target genes in neurons.
**Clinical Implications:** This study identifies a mechanistic link between maladaptive innate immune activation and loss of cognitive resilience in tauopathy. The cGAS-STING-IFN axis in microglia suppresses the neuronal MEF2C transcriptional network, rendering the brain vulnerable to tau-induced cognitive decline. Pharmacological inhibition of cGAS with a brain-penetrant compound (TDI-6570) enhanced MEF2C target gene expression and rescued synaptic and cognitive deficits without affecting tau pathology, supporting a strategy to boost cognitive resilience rather than clear pathological protein aggregates. Given that Cgas-/- mice are healthy and fertile, and that STING activation is implicated in other neurodegenerative diseases (Parkinson's, Huntington's, ALS), targeting cGAS represents a promising therapeutic approach for AD and potentially other proteinopathies.