Title | Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Udeochu 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 |
Journal | Nat Neurosci |
Volume | 26 |
Issue | 5 |
Pagination | 737-750 |
Date Published | 2023 May |
ISSN | 1546-1726 |
Keywords | Animals, Cognition, Immunity, Innate, Interferons, MEF2 Transcription Factors, Mice, Microglia, Nucleotidyltransferases, tau Proteins |
Abstract | 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. |
DOI | 10.1038/s41593-023-01315-6 |
Alternate Journal | Nat Neurosci |
PubMed ID | 37095396 |
PubMed Central ID | PMC10166855 |
Grant List | K12 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 |