biostudies-literatureUdeochu JCTau Consortium CureAD Fund Daedalus FundNICHD NIH HHSNIA NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on AgingCureAD Fund Daedalus FundJumpStart Research Career Development Program, Weill Cornell MedicineBrightFocus FoundationJPB FoundationU.S. Department of Health & Human Services | National Institutes of HealthBoston Children’s Hospital737-750https://www.ebi.ac.uk/biostudies/studies/S-EPMC10166855biostudies-literatureUnknown26(5)Pathological hallmarks of Alzheimer's 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 mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, thNature neuroscienceTau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.PMC101668555K12HD052896A20201312FK01 AG057862R01AG064239R01AG072758K12 HD052896T32 HD098061R01 AG074541R01AG054214R01 AG054214R01AG074541R01 AG072758R01 AG064239Gong SCorona CRaju RMZhao MYarahmady ASinha SCKauwe GFan LMok SANagiri RKWong MYTorres ERSTracy TEUdeochu JCLo ICarling GKMcGurran HCoronas-Samano GMousa GAGill MTHuang YYe PRatan RRGan LAmin SLuo WLiu BTsai LHHoltzman JfalseTau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.Pathological hallmarks of Alzheimer's 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 mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, th2023-01-01T00:00:00Z2023 May2026-05-28T19:51:32.847Z2024-11-21T05:38:25.605ZS-EPMC101668553709539610.1038/s41593-023-01315-6