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mTOR-dependent translation amplifies microglia priming in aging mice

Keane, Lily; Antignano, Ignazio; Riechers, Sean-Patrick; Zollinger, Raphael; Dumas, Anaelle A; Offermann, Nina; Bernis, Maria E; ... Capasso, Melania; + view all (2021) mTOR-dependent translation amplifies microglia priming in aging mice. Journal of Clinical Investigation , 131 (1) , Article e132727. 10.1172/JCI132727. Green open access

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Abstract

Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice had upregulated mTOR complex 1 signaling controlling translation, as well as protein levels of inflammatory mediators. Genetic ablation of mTOR signaling showed a dual yet contrasting effect on microglia priming: It caused an NF-κB-dependent upregulation of priming genes at the mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation, and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1, resulting in decreased binding of eIF4E to eIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating that upregulation of mTOR-dependent translation is an essential aspect of microglia priming in aging and neurodegeneration.

Type: Article
Title: mTOR-dependent translation amplifies microglia priming in aging mice
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/JCI132727
Publisher version: https://doi.org/10.1172/JCI132727
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Medicine, Research & Experimental, Research & Experimental Medicine, INITIATION-FACTOR 4E, PROTEIN-SYNTHESIS, MAMMALIAN TARGET, LIFE-SPAN, COMPLEX 1, PHOSPHORYLATION, KINASE, EIF4E, RHEB, BINDING
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10165034
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