Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Republic of Korea.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Brain Behav Immun. 2019 Aug;80:344-357. doi: 10.1016/j.bbi.2019.04.011. Epub 2019 Apr 11.
Aggregation of the microtubule-associated protein, tau, can lead to neurofibrillary tangle formation in neurons and glia which is the hallmark of tauopathy. The cellular damage induced by the formation of neurofibrillary tangles leads to neuroinflammation and consecutive neuronal death. However, detailed observation of transcriptomic changes under tauopathy together with the comparison of age-dependent progression of neuroinflammatory gene expressions mediated by tau overexpression is required. Employing RNA sequencing on PS19 transgenic mice that overexpress human mutant tau harboring the P301S mutation, we have examined the effects of age-dependent tau overexpression on transcriptomic changes of immune and inflammatory responses in the cerebral cortex. Compared to age-matched wild type control, P301S transgenic mice exhibit significant transcriptomic alterations. We have observed age-dependent neuroinflammatory gene expression changes in both wild type and P301S transgenic mice where tau overexpression further promoted the expression of neuroinflammatory genes in 10-month old P301S transgenic mice. Moreover, functional gene network analyses (gene ontology and pathway enrichment) and prospective target protein interactions predicted the potential involvement of multiple immune and inflammatory pathways that may contribute to tau-mediated neuronal pathology. Our current study on P301S transgenic mice model revealed for the first time, the differences of gene expression patterns in both early and late stage of tau pathology in cerebral cortex. Our analyses also revealed that tau overexpression alone induces multiple inflammatory and immune transcriptomic changes and may provide a roadmap to elucidate the targets of anti-inflammatory therapeutic strategy focused on tau pathology and related neurodegenerative diseases.
微管相关蛋白 tau 的聚集可导致神经元和神经胶质中的神经原纤维缠结形成，这是 tau 病的标志。神经原纤维缠结的形成所诱导的细胞损伤导致神经炎症和随后的神经元死亡。然而，需要详细观察 tau 病下的转录组变化，并比较tau 过表达介导的神经炎症基因表达的年龄依赖性进展。我们使用 RNA 测序研究了过表达携带 P301S 突变的人突变 tau 的 PS19 转基因小鼠，以检查年龄依赖性 tau 过表达对大脑皮层免疫和炎症反应转录组变化的影响。与年龄匹配的野生型对照相比，P301S 转基因小鼠表现出显著的转录组改变。我们观察到野生型和 P301S 转基因小鼠的神经炎症基因表达随年龄的变化，tau 过表达进一步促进了 10 个月大的 P301S 转基因小鼠中神经炎症基因的表达。此外，功能基因网络分析（基因本体论和途径富集）和前瞻性靶蛋白相互作用预测了多个免疫和炎症途径的潜在参与，这些途径可能有助于 tau 介导的神经元病理学。我们在 P301S 转基因小鼠模型上的当前研究首次揭示了大脑皮层中 tau 病理学的早期和晚期基因表达模式的差异。我们的分析还表明，tau 过表达本身可诱导多种炎症和免疫转录组变化，并可能为阐明针对 tau 病理学和相关神经退行性疾病的抗炎治疗策略的靶点提供路线图。
