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

Foteini Vasilopoulou; Thomas M Piers; Jingzhang Wei; John Hardy; Jennifer M Pocock

doi:10.1111/febs.17353

Amelioration of signaling deficits underlying metabolic shortfall in TREM2^R47H human iPSC-derived microglia

FEBS J. 2024 Dec 26. doi: 10.1111/febs.17353. Online ahead of print.

Authors

Foteini Vasilopoulou¹, Thomas M Piers¹, Jingzhang Wei¹, John Hardy^{2

3

4

5}, Jennifer M Pocock¹

Affiliations

¹ Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London, UK.
² Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
³ UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, UK.
⁴ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
⁵ NIHR University College London Hospitals Biomedical Research Centre and Institute for Advanced Study, The Hong Kong University of Science and Technology, China.

PMID: 39726135
DOI: 10.1111/febs.17353

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) TREM2^R47H hypomorph display several functional deficits linked to metabolism. To investigate whether these deficits are associated with disruptions in metabolite signaling, we generated common variant, TREM2^R47H 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 TREM2^R47H 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.

Keywords: Alzheimer's disease; R47H TREM2 variant; TCA‐metabolites; human microglia; metabolism; neurodegeneration.

Abstract

Grants and funding