TY  - JOUR
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
TI  - mTOR-dependent translation amplifies microglia priming in aging mice
JO  - The journal of clinical investigation
VL  - 131
IS  - 1
SN  - 1558-8238
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DZNE-2021-00002
SP  - e132727
PY  - 2021
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.
KW  - Aging: genetics
KW  - Aging: metabolism
KW  - Animals
KW  - Eukaryotic Initiation Factor-4E: genetics
KW  - Eukaryotic Initiation Factor-4E: metabolism
KW  - Eukaryotic Initiation Factor-4G: genetics
KW  - Eukaryotic Initiation Factor-4G: metabolism
KW  - Humans
KW  - Mice
KW  - Mice, Transgenic
KW  - Microglia: enzymology
KW  - NF-kappa B: genetics
KW  - NF-kappa B: metabolism
KW  - Phosphorylation: genetics
KW  - Protein Biosynthesis
KW  - Signal Transduction
KW  - TOR Serine-Threonine Kinases: genetics
KW  - TOR Serine-Threonine Kinases: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7773382
C6  - pmid:33108356
DO  - DOI:10.1172/JCI132727
UR  - https://pub.dzne.de/record/153985
ER  -