학술논문
Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease
Document Type
Original Paper
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
Source
Nature Neuroscience. 26(7):1196-1207
Subject
Language
English
ISSN
1097-6256
1546-1726
1546-1726
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.
Yin et al. identify miR-155–IFN-γ signaling that regulates a protective microglial subset in a mouse model of Alzheimer’s disease. These microglia enhance plaque compaction, reduce dystrophic neurites and synaptic degradation, and improve cognition.
Yin et al. identify miR-155–IFN-γ signaling that regulates a protective microglial subset in a mouse model of Alzheimer’s disease. These microglia enhance plaque compaction, reduce dystrophic neurites and synaptic degradation, and improve cognition.