Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Neurosci. 2023 Jul;26(7):1196-1207. doi: 10.1038/s41593-023-01355-y. Epub 2023 Jun 8.
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.
小胶质细胞在大脑内稳态和疾病进展中发挥着关键作用。在神经退行性疾病中，小胶质细胞获得神经退行性表型（MGnD），但其功能尚未完全阐明。富含于免疫细胞中的 microRNA-155（miR-155）对 MGnD 具有关键的调控作用。然而，其在阿尔茨海默病（AD）发病机制中的作用仍不清楚。本研究报告称，小胶质细胞中 miR-155 的缺失通过干扰素-γ（IFN-γ）信号诱导前 MGnD 激活状态，阻断 IFN-γ 信号可减弱 MGnD 的诱导和小胶质细胞的吞噬作用。AD 小鼠模型中小胶质细胞的单细胞 RNA 测序分析鉴定出 Stat1 和 Clec2d 为前 MGnD 标志物。这种表型转变增强了淀粉样斑块的紧致度，减少了萎缩性神经突，减弱了斑块相关的突触降解，并改善了认知功能。本研究证实了 miR-155 介导的 MGnD 调控机制，以及 IFN-γ 反应性前 MGnD 在限制 AD 小鼠模型中神经退行性病变和保护认知功能方面的有益作用，强调了 miR-155 和 IFN-γ 作为 AD 潜在治疗靶点的重要性。
