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

doi:10.1038/s41593-023-01355-y

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Nature Neuroscience. 2023-06-08, vol. 26, n° 7, p. 1196-1207

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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.< Leer menos

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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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