TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia

BioRxiv : the Preprint Server for Biology
Amit JairamanMichael Cahalan


The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss?of?function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD). Because abnormalities in Ca2+ signaling have been observed in several AD models, we investigated TREM2 regulation of Ca2+ signaling via genetic deletion in human induced pluripotent stem cell-derived microglia (iPSC microglia). We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca2+ signals in response to purinergic agonists such as ADP that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y12 and P2Y13 receptors, results in sustained Ca2+ influx and alters cell motility and process extension in TREM2 KO microglia. In a 'Ca2+ clamp' assay using iPSC-microglia expressing the genetically encoded Ca2+ probe, Salsa6f, we found that cytosolic Ca2+ tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic C...Continue Reading

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