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Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
mTOR-dependent translation amplifies microglia priming in aging mice
Lily Keane1,2, Ignazio Antignano1, Sean-Patrick Riechers1
1German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
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.
Insights
Microglia priming in aging brains involves increased mTOR signaling, leading to more inflammation. Inhibiting this pathway reduced inflammatory proteins and sickness behavior, suggesting a therapeutic target for neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Microglia are key immune cells in the brain, crucial for maintaining homeostasis.
- With aging, microglia become primed, exhibiting heightened inflammatory responses.
- This priming is linked to neurodegenerative conditions and age-related cognitive decline.
Purpose of the Study:
- To investigate the role of mTOR complex 1 (mTORC1) signaling in microglia priming during aging.
- To determine the impact of genetic ablation of mTORC1 signaling on microglia activation and associated behaviors.
- To explore the translational control mechanisms underlying microglia priming.
Main Methods:
- Analysis of mTORC1 signaling, translation, and inflammatory mediator protein levels in microglia from aged mice.
- Genetic deletion of mTOR signaling components in mice.
- Assessment of NF-κB pathway activation, cytokine production, microglia activation markers, and sickness behavior.
- Investigation of 4EBP1 phosphorylation and eIF4E/eIF4G binding.
Main Results:
- Aged microglia exhibit upregulated mTORC1 signaling, controlling translation and increasing inflammatory mediators.
- Genetic ablation of mTORC1 signaling had a dual effect: increased mRNA of priming genes but decreased cytokine protein levels and microglia activation.
- Reduced mTORC1 signaling decreased 4EBP1 phosphorylation, impairing eIF4E/eIF4G binding and translation.
- Similar mTOR-dependent translational changes were observed in aged human microglia and damage-associated microglia.
Conclusions:
- Upregulated mTOR-dependent translation is a critical component of microglia priming in aging and neurodegeneration.
- Targeting mTORC1 signaling in microglia presents a potential therapeutic strategy for age-related neuroinflammation.
- Modulating microglia translation offers a novel approach to mitigate neurodegenerative processes.
