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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Updated: Jul 27, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Zhuoran Yin1,2, Shawn Herron3, Sebastian Silveira1
1Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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.
Insights
Microglia
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are key immune cells in the brain, crucial for homeostasis and disease.
- The neurodegenerative microglia phenotype (MGnD) is poorly understood in neurodegenerative diseases.
- MicroRNA-155 (miR-155) regulates MGnD, but its role in Alzheimer's disease (AD) is unclear.
Purpose of the Study:
- To investigate the role of miR-155 in regulating MGnD in Alzheimer's disease.
- To elucidate the signaling pathways involved in MGnD induction.
- To assess the therapeutic potential of targeting miR-155 and interferon-γ (IFN-γ) in AD.
Main Methods:
- Utilized a mouse model of Alzheimer's disease.
- Performed microglial-specific deletion of miR-155.
- Employed single-cell RNA-sequencing to identify MGnD markers.
- Analyzed interferon-γ (IFN-γ) signaling pathways.
Main Results:
- Microglial deletion of miR-155 induced a pre-MGnD state via IFN-γ signaling.
- Blocking IFN-γ signaling reduced MGnD and microglial phagocytosis.
- Identified Stat1 and Clec2d as pre-MGnD markers using single-cell RNA-sequencing.
- Observed enhanced amyloid plaque compaction, reduced neurite dystrophy, and improved cognition.
Conclusions:
- miR-155 regulates MGnD through IFN-γ signaling.
- The IFN-γ-responsive pre-MGnD phenotype benefits AD pathology and cognition.
- miR-155 and IFN-γ are potential therapeutic targets for Alzheimer's disease.
