Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer’s disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks. Microglia cells were isolated from rTg4510 tau transgenic mice and gene expression was profiled using RNA sequencing. Four age groups of mice (2-, 4-, 6-, and 8-months) were analyzed to capture longitudinal gene expression changes that correspond to varying levels of pathology, from minimal tau accumulation to massive neuronal loss. Statistical and system biology approaches were used to analyze the genes and pathways that underlie microglia activation. Differentially expressed genes were compared to human brain co-expression networks. Statistical analysis of RNAseq data indicated that more than 4000 genes were differentially expressed in rTg4510 microglia compared to wild type microglia, with the majority of gene expression changes occurring between 2- and 4-months of age. These genes belong to four major clusters based on their temporal expression pattern. Genes involved in innate immunity were continuously up-regulated, whereas genes involved in the glutamatergic synapse were down-regulated. Up-regulated innate inflammatory pathways included NF-κB signaling, cytokine-cytokine receptor interaction, lysosome, oxidative phosphorylation, and phagosome. NF-κB and cytokine signaling were among the earliest pathways activated, likely driven by the RELA, STAT1 and STAT6 transcription factors. The expression of many AD associated genes such as APOE and TREM2 was also altered in rTg4510 microglia cells. Differentially expressed genes in rTg4510 microglia were enriched in human neurodegenerative disease associated pathways, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, and highly overlapped with the microglia and endothelial modules of human brain transcriptional co-expression networks. This study revealed temporal transcriptome alterations in microglia cells in response to pathological tau perturbation and provides insight into the molecular changes underlying microglia activation during tau mediated neurodegeneration.

中文翻译：

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全基因组RNAseq研究rTg4510 tau转基因动物模型中小胶质细胞激活对病理性tau摄动的分子机制

小胶质细胞（中枢神经系统的固有免疫细胞）的激活是阿尔茨海默氏病（AD）的突出病理标志。然而，响应于tau病理学的小胶质细胞激活的基因表达变化仍然难以捉摸。此外，尚不清楚鼠基因表达变化如何与人类基因表达网络相关。从rTg4510 tau转基因小鼠中分离出小胶质细胞，并使用RNA测序分析基因表达。分析了四个年龄组的小鼠（2、4、6、8个月）以捕获纵向基因表达变化，这些变化对应于病理水平的变化，从最小的tau积累到大量神经元丢失。统计和系统生物学方法用于分析构成小胶质细胞激活基础的基因和途径。将差异表达的基因与人脑共表达网络进行了比较。RNAseq数据的统计分析表明，与野生型小胶质细胞相比，rTg4510小胶质细胞中有4000多个基因差异表达，而大多数基因表达变化发生在2到4个月大时。这些基因基于它们的时间表达模式而属于四个主要簇。与先天免疫有关的基因被连续上调，而与谷氨酸能突触有关的基因被下调。上调的先天炎症途径包括NF-κB信号传导，细胞因子-细胞因子受体相互作用，溶酶体，氧化磷酸化和吞噬体。NF-κB和细胞因子信号传导是最早的激活途径，可能由RELA，STAT1和STAT6转录因子驱动。在rTg4510小胶质细胞中，许多与AD相关的基因（如APOE和TREM2）的表达也发生了变化。rTg4510小胶质细胞中差异表达的基因富含人类神经退行性疾病的相关途径，包括阿尔茨海默氏病，帕金森氏病和亨廷顿氏病，并且与人脑转录共表达网络的小胶质细胞和内皮模块高度重叠。这项研究揭示了小胶质细胞对病理性tau摄动的反应中转录组的变化，并为tau介导的神经变性过程中小胶质细胞激活的分子变化提供了见识。rTg4510小胶质细胞中差异表达的基因富含人类神经退行性疾病的相关途径，包括阿尔茨海默氏病，帕金森氏病和亨廷顿氏病，并且与人脑转录共表达网络的小胶质细胞和内皮模块高度重叠。这项研究揭示了小胶质细胞对病理性tau摄动的反应中转录组的变化，并为tau介导的神经变性过程中小胶质细胞激活的分子变化提供了见识。rTg4510小胶质细胞中差异表达的基因富含人类神经退行性疾病的相关途径，包括阿尔茨海默氏病，帕金森氏病和亨廷顿氏病，并且与人脑转录共表达网络的小胶质细胞和内皮模块高度重叠。这项研究揭示了小胶质细胞对病理性tau摄动的反应中转录组的变化，并为tau介导的神经变性过程中小胶质细胞激活的分子变化提供了见识。