Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease
Nat Neurosci. 2023-06-08; 26(7): 1196-1207
DOI: 10.1038/s41593-023-01355-y
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Yin Z(#)(1)(2), Herron S(#)(3), Silveira S(1), Kleemann K(1)(4), Gauthier C(1), Mallah D(1), Cheng Y(1), Margeta MA(1)(5), Pitts KM(1)(5), Barry JL(1), Subramanian A(6)(7), Shorey H(1), Brandao W(1), Durao A(1), Delpech JC(3)(8), Madore C(1)(8), Jedrychowski M(9), Ajay AK(10), Murugaiyan G(1), Hersh SW(3), Ikezu S(3)(11), Ikezu T(12)(13), Butovsky O(14)(15).
Author information:
(1)Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
(2)Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
(3)Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
(4)School of Computing, University of Portsmouth, Portsmouth, UK.
(5)Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
(6)Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
(7)ARCND, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
(8)Laboratoire NutriNeuro, UMR 1286, Bordeaux INP, INRAE, University of Bordeaux, Bordeaux, France.
(9)Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA. (10)Department of Medicine, Division of Renal Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA, USA.
(11)Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
(12)Department of Pharmacology and Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. .
(13)Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
.
(14)Department of Neurology, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA. .
(15)Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA. .
(#)Contributed equally
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.
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41593-023-01355-y
PMCID: PMC10619638
PMID: 37291336 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests O.B. is an inventor of a
patent for use of miR-155 inhibitors for treatment of neurodegenerative
diseases. O.B.: collaboration with GSK, Regulus Therapeutics; research funding
from Sanofi, GSK, honoraria for lectures, consultancy: Camp4, Ono Pharma USA.
T.I. consults Takeda. The remaining authors declare no competing interests.