Department of Neuroscience, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
Cell Rep. 2022 May 31;39(9):110883. doi: 10.1016/j.celrep.2022.110883.
TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimer's disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. Here, we generate a transgenic mouse model of reduced Trem2 shedding (Trem2-Ile-Pro-Asp [IPD]) through amino-acid substitution of an ADAM-protease recognition site. We show that Trem2-IPD mice display increased Trem2 cell-surface-receptor load, survival, and function in myeloid cells. Using single-cell transcriptomic profiling of mouse cortex, we show that sustained Trem2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Aβ pathology in a mouse model of Alzheimer's disease. Our data indicate that reduction of Trem2 proteolytic cleavage aggravates neuroinflammation during the course of Alzheimer's disease pathology, suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.
TREM2 是一种跨膜蛋白，仅在大脑中的小胶质细胞中表达，可调节对病理状况的炎症反应。膜 TREM2 的蛋白水解裂解影响小胶质细胞功能，与阿尔茨海默病有关，但减少 TREM2 蛋白水解裂解的后果尚未确定。在这里，我们通过 ADAM 蛋白酶识别位点的氨基酸取代生成了一种减少 Trem2 脱落的转基因小鼠模型（Trem2-Ile-Pro-Asp [IPD]）。我们表明，Trem2-IPD 小鼠显示出髓样细胞中增加的 Trem2 细胞表面受体负荷、存活和功能。使用小鼠大脑皮层的单细胞转录组分析，我们表明，持续的 Trem2 稳定化诱导小胶质细胞成熟命运的转变，并加速阿尔茨海默病小鼠模型中 Aβ 病理学的小胶质细胞反应。我们的数据表明，Trem2 蛋白水解裂解的减少加剧了阿尔茨海默病病理过程中的神经炎症，表明 TREM2 脱落是病理状态中小胶质细胞活性的关键调节剂。
