Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience I

Analysis of differentially expressed genes (DEGs) revealed a striking upregulation of interferon genes in P301S, compared to non-transgenic hippocampi, and enrichment of transcription factor motifs of interferon-response factors (IRFs) and interferon-sensitive response elements (ISREs). Cgas deletion reduced the induction of a subset of tau-stimulated inflammatory and cytokine expression including interferon stimulated genes such as Stat1, Ddx60, Isg20, Rnf213, Parp12, Ifi35, and Sp100. Thus, microglial cGAS promotes IFN-I expression in response to tau. Overall design: To characterize gene expression changes associated with tauopathy, we performed bulk RNA sequencing of P301S tau transgenic and non-transgenic hippocampi (8–9 months) . To determine if cGAS mediates tau-induced interferon responses, we treated Cgas-/- and Cgas+/+ primary microglia with tau fibrils or herring testis DNA (HT-DNA) and performed RNA sequencing.