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

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, Alexander Kertser, Kuti Baruch, Neta Rosenzweig, Anna Terem, Marco Prinz, Saul Villeda, Ami Citri, Ido Amit () and Michal Schwartz ()
Additional contact information
Aleksandra Deczkowska: Weizmann Institute of Science
Orit Matcovitch-Natan: 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
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
Marco Prinz: Institute of Neuropathology, Faculty of Medicine, University of Freiburg
Saul Villeda: University of California San Francisco
Ami Citri: Institute of Life Sciences, Faculty of Natural Sciences, The Hebrew University
Ido Amit: Weizmann Institute of Science
Michal Schwartz: Weizmann Institute of Science

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00769-0

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