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A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia
Thomas M Piers1, Katharina Cosker1, Anna Mallach1
1Department of Neuroinflammation, University College London Queen Square Institute of Neurology, London, UK.
Abstract:
Loss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC-derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.
Insights
Loss-of-function variants in triggering receptor expressed on myeloid cells 2 (TREM2) impair microglial metabolism, hindering their function in dementia. Targeting PPARγ/p38MAPK signaling can restore metabolic health and improve amyloid clearance.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Loss-of-function genetic variants in TREM2 increase dementia risk.
- Microglia, brain immune cells expressing TREM2, are crucial in neuroinflammation and dementia.
- Microglial function relies on metabolic flexibility, switching between oxidative phosphorylation and glycolysis.
Purpose of the Study:
- To investigate the impact of TREM2 variants on microglial metabolic function.
- To identify the molecular mechanisms underlying metabolic deficits in TREM2 variant microglia.
- To explore therapeutic strategies for restoring microglial function in TREM2-associated dementia.
Main Methods:
- Utilized human induced pluripotent stem cell (iPSC)-derived microglia with TREM2 loss-of-function variants.
- Assessed mitochondrial respiratory capacity and glycolytic function.
- Analyzed PPARγ/p38MAPK signaling pathways.
- Evaluated β-Amyloid phagocytosis as a measure of microglial function.
Main Results:
- TREM2 variant iPSC-microglia displayed reduced mitochondrial respiration.
- These cells showed an impaired ability to switch to glycolysis (glycolytic immunometabolic switch).
- Dysregulated PPARγ/p38MAPK signaling was identified as the cause of metabolic deficits.
- Activating these pathways rescued metabolic function and improved β-Amyloid phagocytosis.
Conclusions:
- TREM2 variants disrupt microglial metabolic homeostasis, impacting their immune functions.
- PPARγ/p38MAPK signaling is a key regulator of TREM2-dependent microglial metabolism.
- Targeting PPARγ/p38MAPK pathways offers a potential therapeutic avenue for dementia associated with TREM2 variants.
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