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

Author

Listed:
  • Aleksandra Deczkowska

    (Weizmann Institute of Science)

  • Orit Matcovitch-Natan

    (Weizmann Institute of Science
    Weizmann Institute of Science)

  • Afroditi Tsitsou-Kampeli

    (Weizmann Institute of Science)

  • Sefi Ben-Hamo

    (Weizmann Institute of Science)

  • Raz Dvir-Szternfeld

    (Weizmann Institute of Science)

  • Amit Spinrad

    (Weizmann Institute of Science
    Weizmann Institute of Science)

  • Oded Singer

    (Faculty of Biochemistry, Life Sciences Core Facilities, Weizmann Institute of Science)

  • Eyal David

    (Weizmann Institute of Science)

  • Deborah R. Winter

    (Weizmann Institute of Science)

  • Lucas K. Smith

    (University of California San Francisco)

  • Alexander Kertser

    (Weizmann Institute of Science)

  • Kuti Baruch

    (Weizmann Institute of Science)

  • Neta Rosenzweig

    (Weizmann Institute of Science)

  • Anna Terem

    (Institute of Life Sciences, Faculty of Natural Sciences, The Hebrew University
    Edmond and Lily Safra Center for Brain Sciences, The Hebrew University)

  • Marco Prinz

    (Institute of Neuropathology, Faculty of Medicine, University of Freiburg
    BIOSS Centre for Biological Signalling Studies, University of Freiburg)

  • Saul Villeda

    (University of California San Francisco)

  • Ami Citri

    (Institute of Life Sciences, Faculty of Natural Sciences, The Hebrew University
    Edmond and Lily Safra Center for Brain Sciences, The Hebrew University)

  • Ido Amit

    (Weizmann Institute of Science)

  • Michal Schwartz

    (Weizmann Institute of Science)

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.

Suggested Citation

  • Aleksandra Deczkowska & Orit Matcovitch-Natan & Afroditi Tsitsou-Kampeli & Sefi Ben-Hamo & Raz Dvir-Szternfeld & Amit Spinrad & Oded Singer & Eyal David & Deborah R. Winter & Lucas K. Smith & Alexande, 2017. "Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00769-0
    DOI: 10.1038/s41467-017-00769-0
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    Cited by:

    1. Fei Wang & Peiwen Ding & Xue Liang & Xiangning Ding & Camilla Blunk Brandt & Evelina Sjöstedt & Jiacheng Zhu & Saga Bolund & Lijing Zhang & Laura P. M. H. Rooij & Lihua Luo & Yanan Wei & Wandong Zhao , 2022. "Endothelial cell heterogeneity and microglia regulons revealed by a pig cell landscape at single-cell level," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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