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

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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

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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