Nature neuroscience · 29 authors, 8 centres
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In tauopathy mouse models, pathogenic tau activates cGAS in microglia, triggering a type I interferon response that suppresses the neuronal MEF2C transcriptional network associated with cognitive resilience. Genetic ablation of Cgas or pharmacological inhibition with TDI-6570 preserved synaptic integrity, plasticity, and memory without reducing tau load.
This preclinical study used P301S tauopathy mice, primary microglia cultures, and human AD brain samples to investigate how cGAS activation in microglia influences cognitive resilience. The authors demonstrated that pathogenic tau induces cGAS activation in microglia, partly through cytosolic leakage of mitochondrial DNA, triggering an IFN-I response. Genetic ablation of Cgas in tauopathy mice diminished the microglial IFN-I response, enhanced the neuronal MEF2C transcriptional network, and preserved synapse integrity and plasticity while protecting against cognitive impairment, without affecting tau load. Pharmacological inhibition of cGAS with TDI-6570 similarly enhanced MEF2C target gene expression and restored synaptic integrity, plasticity, and memory. snRNA-seq analyses of human AD brains revealed an association between elevated microglial IFN-I genes and reduced neuronal MEF2C expression.
