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Amelioration of signaling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia
Foteini Vasilopoulou1, Thomas M Piers1, Jingzhang Wei1
1Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London, UK.
Abstract:
The microglial triggering receptor expressed on myeloid cells 2 (TREM2) is required for diverse microglia responses in neurodegeneration, including immunometabolic plasticity, phagocytosis, and survival. We previously identified that patient iPSC-derived microglia (iPS-Mg) harboring the Alzheimer's disease (AD) TREM2R47H hypomorph display several functional deficits linked to metabolism. To investigate whether these deficits are associated with disruptions in metabolite signaling, we generated common variant, TREM2R47H and TREM2-/- variant human iPS-Mg. We assessed the ability of supplementation with citrate or succinate, key metabolites and cell cycle breaking points upon microglia activation, to overcome these functional deficits with potential impact on neurons. Succinate supplementation was more effective than citrate at overcoming mitochondrial deficits in OXPHOS and did not promote a glycolytic switch. Citrate enhanced the lipid content of TREM2R47H iPS-Mg and was more effective at overcoming Αβ phagocytic deficits, whereas succinate increased lipid content and phagocytic capacity in TREM2-/- iPS-Mg. Microglia cytokine secretion upon pro-inflammatory activation was moderately affected by citrate or succinate showing a condition-dependent increasing trend. Neither metabolite altered basal levels of soluble TREM2 shedding. In addition, neither citrate nor succinate enhanced glycolysis; instead, drove their effects through oxidative phosphorylation. IPS-neurons exposed to conditioned medium from TREM2 variant iPS-Mg showed changes in oxidative phosphorylation, which could be ameliorated when iPS-Mg were first treated with citrate or succinate. Our data point to discrete pathway linkage between microglial metabolism and functional outcomes with implications for AD pathogenesis and treatments.
Insights
Supplementing microglia with specific metabolites, citrate or succinate, can address functional deficits linked to Alzheimer's disease (AD) TREM2 variants, impacting neuroinflammation and neuronal health.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Microglial triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for microglial function in neurodegeneration.
- Alzheimer's disease (AD) TREM2 variants, like R47H, are associated with microglial metabolic and functional deficits.
- Understanding these metabolic disruptions is key to developing targeted AD therapies.
Purpose of the Study:
- To investigate if metabolite supplementation can rescue functional deficits in iPSC-derived microglia (iPS-Mg) with AD-associated TREM2 variants.
- To determine the impact of citrate and succinate on mitochondrial function, phagocytosis, and cytokine secretion in TREM2-variant iPS-Mg.
- To assess the downstream effects on neurons exposed to conditioned media from treated iPS-Mg.
Main Methods:
- Generation of human iPS-Mg from common variant, TREM2R47H, and TREM2-/- variants.
- Supplementation with citrate or succinate to assess rescue of metabolic and functional deficits.
- Analysis of mitochondrial oxidative phosphorylation (OXPHOS), glycolysis, lipid content, phagocytosis, and cytokine secretion.
- Exposure of iPSC-derived neurons to conditioned media from treated iPS-Mg to evaluate neuronal function.
Main Results:
- Succinate supplementation effectively improved mitochondrial OXPHOS deficits without promoting glycolysis.
- Citrate enhanced lipid content and phagocytosis in TREM2R47H iPS-Mg, while succinate boosted these in TREM2-/- iPS-Mg.
- Metabolite supplementation improved neuronal oxidative phosphorylation affected by TREM2-variant iPS-Mg conditioned media.
- Neither metabolite altered soluble TREM2 shedding or basal glycolysis, with effects mediated via OXPHOS.
Conclusions:
- Citrate and succinate differentially impact microglial function and metabolism in TREM2-variant models of AD.
- Metabolite supplementation offers a potential therapeutic strategy to mitigate microglial dysfunction in AD pathogenesis.
- Targeting microglial metabolic pathways presents a promising avenue for AD treatment development.
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