Aging/genetics/metabolism; Animals; Eukaryotic Initiation Factor-4E/genetics/metabolism; Eukaryotic Initiation Factor-4G/genetics/metabolism; Humans; Mice; Mice, Transgenic; Microglia/enzymology; NF-kappa B/genetics/metabolism; Phosphorylation/genetics; Protein Biosynthesis; Signal Transduction; TOR Serine-Threonine Kinases/genetics/metabolism; Aging; Cytokines; Inflammation; Macrophages; Translation
Résumé :
[en] 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.
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