mTOR-dependent translation amplifies microglia priming in aging mice.

Keane, Lily; Antignano, Ignazio; RIECHERS, Sean-Patrick Hermann; Zollinger, Raphael; Dumas, Anaelle A.; Offermann, Nina; Bernis, Maria E.; Russ, Jenny; Graelmann, Frederike; McCormick, Patrick Neil; Esser, Julia; Tejera, Dario; Nagano, Ai; Wang, Jun; Chelala, Claude; Biederbick, Yvonne; Halle, Annett; Salomoni, Paolo; HENEKA, Michael; Capasso, Melania

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mTOR-dependent translation amplifies microglia priming in aging mice.

Keane, Lily; Antignano, Ignazio; RIECHERS, Sean-Patrick Hermann et al.

2021 • In Journal of Clinical Investigation, 131 (1)

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Keywords :

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

Abstract :

[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.

Disciplines :

Neurology

Author, co-author :

Keane, Lily

Antignano, Ignazio

RIECHERS, Sean-Patrick Hermann ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Zollinger, Raphael

Dumas, Anaelle A.

Offermann, Nina

Bernis, Maria E.

Russ, Jenny

Graelmann, Frederike

McCormick, Patrick Neil

More authors (10 more)

External co-authors :

yes

Language :

English

Title :

mTOR-dependent translation amplifies microglia priming in aging mice.

Publication date :

2021

Journal title :

Journal of Clinical Investigation

ISSN :

0021-9738

eISSN :

1558-8238

Volume :

131

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBilu :

since 13 October 2023

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