Microglia play important roles in maintaining brain homeostasis and neurodegeneration. The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, such as Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), as the strongest risk factors for Alzheimer’s disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of several microglial proteins are poorly conserved across species, which has hampered the development of strategies aiming to modulate the expression of specific microglial genes. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs). In this study, we identified, produced, and tested novel, selective and potent ASOs for human APOE and TREM2. We used a combination of in vitro iPSC-microglia models, as well as microglial xenotransplanted mice to provide proof of activity in human microglial in vivo. We proved their efficacy in human iPSC microglia in vitro, as well as their pharmacological activity in vivo in a xenografted microglia model. We demonstrate ASOs targeting human microglia can modify their transcriptional profile and their response to amyloid-β plaques in vivo in a model of AD. This study is the first proof-of-concept that human microglial can be modulated using ASOs in a dose-dependent manner to manipulate microglia phenotypes and response to neurodegeneration in vivo.

中文翻译：

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通过 RNAase-H 活性反义寡核苷酸在阿尔茨海默病体内调节人小胶质细胞基因表达和功能

小胶质细胞在维持大脑稳态和神经退行性变中发挥重要作用。主要或专门在骨髓细胞中表达的基因中发现遗传变异，例如载脂蛋白 E (APOE) 和骨髓细胞表达的触发受体 2 (TREM2)，作为阿尔茨海默病 (AD) 的最强危险因素，凸显了小胶质细胞的重要性大脑中的生物学。几种小胶质细胞蛋白的序列、结构和功能在物种间保守性较差，这阻碍了旨在调节特定小胶质细胞基因表达的策略的开发。靶向 APOE 和 TREM2 的一种方法是使用反义寡核苷酸 (ASO) 调节它们的表达。在这项研究中，我们鉴定、生产和测试了针对人类 APOE 和 TREM2 的新型、选择性和有效的 ASO。我们结合使用体外 iPSC-小胶质细胞模型以及小胶质细胞异种移植小鼠来提供人类小胶质细胞体内活性的证据。我们在体外证明了它们在人 iPSC 小胶质细胞中的功效，以及在异种移植小胶质细胞模型中的体内药理活性。我们证明，在 AD 模型中，针对人类小胶质细胞的 ASO 可以改变其转录谱及其对体内淀粉样蛋白斑块的反应。这项研究首次证明了可以使用 ASO 以剂量依赖性方式调节人类小胶质细胞，以操纵小胶质细胞表型和对体内神经变性的反应。