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Nat Commun. 2017 Sep 28;8(1):717. doi: 10.1038/s41467-017-00769-0.

Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner.

Author information

1
Department of Neurobiology, Weizmann Institute of Science, Rehovot, 7610001, Israel.
2
Department of Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel.
3
Faculty of Biochemistry, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, 7610001, Israel.
4
Department of Anatomy, University of California San Francisco, San Francisco, CA, 94143, USA.
5
Department of Biological Chemistry, Institute of Life Sciences, Faculty of Natural Sciences, The Hebrew University, Jerusalem, 91904, Israel.
6
Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, 91904, Israel.
7
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany.
8
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, 79104, Germany.
9
Department of Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel. Ido.Amit@weizmann.ac.il.
10
Department of Neurobiology, Weizmann Institute of Science, Rehovot, 7610001, Israel. Michal.Schwartz@weizmann.ac.il.

Abstract

During ageing, microglia acquire a phenotype that may negatively affect brain function. Here we show that ageing microglial phenotype is largely imposed by interferon type I (IFN-I) chronically present in aged brain milieu. Overexpression of IFN-β in the CNS of adult wild-type mice, but not of mice lacking IFN-I receptor on their microglia, induces an ageing-like transcriptional microglial signature, and impairs cognitive performance. Furthermore, we demonstrate that age-related IFN-I milieu downregulates microglial myocyte-specific enhancer factor 2C (Mef2C). Immune challenge in mice lacking Mef2C in microglia results in an exaggerated microglial response and has an adverse effect on mice behaviour. Overall, our data indicate that the chronic presence of IFN-I in the brain microenvironment, which negatively affects cognitive function, is mediated via modulation of microglial activity. These findings may shed new light on other neurological conditions characterized by elevated IFN-I signalling in the brain.Microglia cells in the brain regulate immune responses, but in ageing can negatively affect brain function. Here the authors show that the chronic presence of type I interferon in aged mouse brain impedes cognitive ability by altering microglia transcriptome and limiting Mef2C, a microglia 'off' signal.

PMID:
28959042
PMCID:
PMC5620041
DOI:
10.1038/s41467-017-00769-0
[Indexed for MEDLINE]
Free PMC Article

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