Tau 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, 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. © 2023. The Author(s).

Citation

Joe C Udeochu, Sadaf Amin, Yige Huang, Li Fan, Eileen Ruth S Torres, Gillian K Carling, Bangyan Liu, Hugo McGurran, Guillermo Coronas-Samano, Grant Kauwe, Gergey Alzaem Mousa, Man Ying Wong, Pearly Ye, Ravi Kumar Nagiri, Iris Lo, Julia Holtzman, Carlo Corona, Allan Yarahmady, Michael T Gill, Ravikiran M Raju, Sue-Ann Mok, Shiaoching Gong, Wenjie Luo, Mingrui Zhao, Tara E Tracy, Rajiv R Ratan, Li-Huei Tsai, Subhash C Sinha, Li Gan. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. Nature neuroscience. 2023 May;26(5):737-750

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PMID: 37095396

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