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bioRxiv · 10.1101/2024.02.12.579896

Amelioration of signalling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia

Vasilopoulou, F.·Piers, T. M.·Jingzhang, W.·Hardy, J.·Pocock, J. M.
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Abstract

Classic immunometabolic switching from oxidative phosphorylation (OXPHOS) to glycolysis occurs in myeloid cells such as microglia when encountering pathogenic insults. We previously showed that patient iPSC-derived microglia (iPS-Mg) harbouring the Alzheimers disease (AD) TREM2R47H hypomorph display deficits in the ability to metabolically switch from OXPHOS to glycolysis, with both reduced mitochondrial maximal respiration and glycolytic capacity. To resolve this, we generated common variant, TREM2R47H and TREM2-/- variant human iPS-Mg and we assessed the ability of supplementation with citrate or succinate, key metabolites and cell cycle breaking points upon microglia activation, to overcome deficits in a number of functions we identified previously as affected by TREM2 loss of function phenotypes. Succinate supplementation was more effective than citrate at overcoming mitochondrial deficits in OXPHOS and did not promote a switch to glycolysis. Citrate enhanced the lipid content of TREM2R47H iPS-Mg and was more effective at overcoming phagocytic deficits whereas succinate increased lipid content and phagocytic capacity in TREM2-/- iPS-Mg. Microglia cytokine release upon activation was differentially affected by citrate or succinate and neither metabolite altered soluble TREM2 shedding. Neither citrate nor succinate enhanced glycolysis but drove their effects through oxidative phosphorylation. Our data point to discrete pathway linkage between microglial metabolism and functional outcomes with implications for AD pathogenesis and treatments.

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Vasilopoulou, F., Piers, T. M., Jingzhang, W., Hardy, J., Pocock, J. M.. 2024-02-12. Amelioration of signalling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia. https://doi.org/10.1101/2024.02.12.579896

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