TY - JOUR
T1 - mTOR-dependent translation amplifies microglia priming in aging mice
AU - Keane, Lily
AU - Antignano, Ignazio
AU - Riechers, Sean Patrick
AU - Zollinger, Raphael
AU - Dumas, Anaelle A.
AU - Offermann, Nina
AU - Bernis, Maria E.
AU - Russ, Jenny
AU - Graelmann, Frederike
AU - McCormick, Patrick Neil
AU - Esser, Julia
AU - Tejera, Dario
AU - Nagano, Ai
AU - Wang, Jun
AU - Chelala, Claude
AU - Biederbick, Yvonne
AU - Halle, Annett
AU - Salomoni, Paolo
AU - Heneka, Michael T.
AU - Capasso, Melania
N1 - Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85098857362
U2 - 10.1172/JCI132727
DO - 10.1172/JCI132727
M3 - Article
C2 - 33108356
AN - SCOPUS:85098857362
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - e132727
ER -