小柯机器人

美国哈佛医学院Oleg Butovsky和美国波士顿大学医学院Tsuneya Ikezu共同合作，近期取得重要工作进展。他们研究实现了阿尔茨海默病小鼠模型中miR-155和干扰素-γ信号介导的保护性小胶质细胞状态的鉴定。相关研究成果2023年6月8日在线发表于《自然—神经科学》杂志上。

据介绍，小胶质细胞在大脑稳态和疾病进展中起着至关重要的作用。在神经退行性疾病中，小胶质细胞获得神经退行性表型（MGnD），其功能尚不清楚。在免疫细胞中富集的microRNA-155（miR-155）对MGnD的调节起关键的作用。然而，它在阿尔茨海默病（AD）发病机制中的作用尚不清楚。

研究人员发现，miR-155的小胶质细胞缺失通过干扰素-γ（IFN-γ）信号传导诱导MGnD前激活状态，阻断IFN-γ信号传导减弱MGnD诱导和小胶质细胞吞噬作用。AD小鼠模型小胶质细胞的单细胞RNA测序分析将Stat1和Clec2d鉴定为Pre-MGnD标志物。这种表型转变增强了淀粉样斑块的压实，减少了营养不良神经炎，减轻了斑块相关的突触降解，并改善了认知能力。

总之，这一研究证明了miR-155介导的MGnD调节机制，以及IFN-γ反应性Pre-MGnD在AD小鼠模型中限制神经退行性病理和保持认知功能方面的有益作用，强调miR-155和IFN-γ是AD的潜在治疗靶点。

附：英文原文

Title: Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease

Author: Yin, Zhuoran, Herron, Shawn, Silveira, Sebastian, Kleemann, Kilian, Gauthier, Christian, Mallah, Dania, Cheng, Yiran, Margeta, Milica A., Pitts, Kristen M., Barry, Jen-Li, Subramanian, Ayshwarya, Shorey, Hannah, Brandao, Wesley, Durao, Ana, Delpech, Jean-Christophe, Madore, Charlotte, Jedrychowski, Mark, Ajay, Amrendra K., Murugaiyan, Gopal, Hersh, Samuel W., Ikezu, Seiko, Ikezu, Tsuneya, Butovsky, Oleg

Issue&Volume: 2023-06-08

Abstract: Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces a pre-MGnD activation state via interferon-γ (IFN-γ) signaling, and blocking IFN-γ signaling attenuates MGnD induction and microglial phagocytosis. Single-cell RNA-sequencing analysis of microglia from an AD mouse model identifies Stat1 and Clec2d as pre-MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque-associated synaptic degradation and improves cognition. Our study demonstrates a miR-155-mediated regulatory mechanism of MGnD and the beneficial role of IFN-γ-responsive pre-MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR-155 and IFN-γ as potential therapeutic targets for AD.

DOI: 10.1038/s41593-023-01355-y

Source: https://www.nature.com/articles/s41593-023-01355-y

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex