Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyperresponsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron–microglia cocultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.

中文翻译：

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携带 TREM2 R47H/+ 突变的 iPSC 衍生小胶质细胞具有促炎性并促进突触损失

遗传学研究结果强调了小胶质细胞在阿尔茨海默病 (AD) 等神经退行性疾病病理学中的关键作用。骨髓细胞 2 上表达的小胶质细胞蛋白触发受体 (TREM2) 中的许多突变与患 AD 的风险增加相关，其中最明显的是 R47H/+ 取代。我们采用基因编辑和干细胞模型来深入了解 TREM2 R47H/+ 突变对人类诱导的多能干细胞衍生的小胶质细胞的影响。我们发现转录变化影响许多细胞过程，R47H/+ 细胞表现出促炎基因表达特征。TREM2 R47H/+ 还会导致小胶质细胞运动和多种底物的摄取受损，并使小胶质细胞对炎症刺激过度反应。我们在神经元-小胶质细胞共培养中开发了体外激光诱导损伤模型，发现 TREM2 R47H/+ 小胶质细胞损伤反应受损。此外，移植 TREM2 R47H/+ 小胶质细胞的小鼠大脑表现出突触密度降低，TREM2 R47H/+ 小胶质细胞中多个补体级联成分上调，表明不适当的突触修剪是一种潜在机制。这些发现确定了 TREM2 R47H/+ 突变对小胶质细胞基因表达和功能的许多潜在有害影响，可能是其与 AD 相关的基础。