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

对差异表达基因（differentially expressed genes, DEGs）的分析显示，与非转基因海马体相比，P301S模型小鼠的干扰素基因呈现显著上调，且干扰素应答因子（interferon-response factors, IRFs）的转录因子基序以及干扰素敏感应答元件（interferon-sensitive response elements, ISREs）显著富集。Cgas敲除可减少tau蛋白刺激诱导的部分炎症与细胞因子表达，包括Stat1、Ddx60、Isg20、Rnf213、Parp12、Ifi35及Sp100等干扰素刺激基因。综上，小胶质细胞Cgas可响应tau蛋白刺激，促进I型干扰素（IFN-I）的表达。实验整体设计：为解析与tau蛋白病相关的基因表达变化，我们对8~9月龄的P301S tau转基因小鼠及非转基因小鼠的海马体进行了批量RNA测序（bulk RNA sequencing）。为验证Cgas是否介导tau蛋白诱导的干扰素应答，我们用tau原纤维或鲱鱼睾丸DNA（herring testis DNA, HT-DNA）处理Cgas敲除（Cgas-/-）及野生型（Cgas+/+）原代小胶质细胞，并进行了RNA测序。