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

TitleTau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.
Publication TypeJournal Article
Year of Publication2023
AuthorsUdeochu JC, Amin S, Huang Y, Fan L, Torres ERuth S, Carling GK, Liu B, McGurran H, Coronas-Samano G, Kauwe G, Mousa GAlzaem, Wong MYing, Ye P, Nagiri RKumar, Lo I, Holtzman J, Corona C, Yarahmady A, Gill MT, Raju RM, Mok S-A, Gong S, Luo W, Zhao M, Tracy TE, Ratan RR, Tsai L-H, Sinha SC, Gan L
JournalNat Neurosci
Date Published2023 May
KeywordsAnimals, Cognition, Immunity, Innate, Interferons, MEF2 Transcription Factors, Mice, Microglia, Nucleotidyltransferases, tau Proteins

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, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.

Alternate JournalNat Neurosci
PubMed ID37095396
PubMed Central IDPMC10166855
Grant ListK12 HD052896 / HD / NICHD NIH HHS / United States
R01 AG074541 / AG / NIA NIH HHS / United States
K01 AG057862 / AG / NIA NIH HHS / United States
R01 AG072758 / AG / NIA NIH HHS / United States
R01 AG054214 / AG / NIA NIH HHS / United States
R01 AG064239 / AG / NIA NIH HHS / United States