mTOR-dependent translation amplifies microglia priming in aging mice

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.