Abstract
Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer’s disease, as well as other neurodegenerative disorders. Using a newly developed, highly sensitive reporter cell model, consisting of Jurkat T cells stably overexpressing a reporter gene and a gene encoding TREM2DAP12 fusion protein, we show here that TREM2-dependent signal transduction in response to apoptotic Neuro2a cells is mediated by aminophospholipid ligands, phosphatidylserine and phosphatidylethanolamine, which are not exposed on the intact cell surface, but become exposed upon apoptosis. We also show that signal-transducing TREM2 ligands different from aminophospholipids, which appear to be derived from neurons, might be present in membrane fractions of mouse cerebral cortex. These results may suggest that TREM2 regulates microglial function by transducing intracellular signals from aminophospholipids on apoptotic cells, as well as unidentified ligands in the membranes of the cerebral cortex.
Highlights
Microglia, which are resident myeloid cells in the brain, provide acute and chronic surveillance of damage- and pathogen-associated signals as a part of the innate immune system[1]
We have developed a highly sensitive reporter cell model to monitor signal transduction from triggering receptor expressed on myeloid cells 2 (TREM2), in order to identify the TREM2 ligands on apoptotic and normal cultured cells and to search for other ligands in the brain that may be associated with increased incidence of Alzheimer’s disease (AD)
To establish sensitive and specific reporter cell models to monitor TREM2 signal transduction, RAW264.7, 2B4, and Jurkat cells were stably transfected with reporter genes: nuclear factor of activated T cells (NFAT) promoter element and TREM2DAP12 fusion cDNA corresponding to TREM2 extracellular domain and DNAX-activating protein of 12 kDa (DAP12) transmembrane and cytosolic domain[38,55,56]
Summary
Microglia, which are resident myeloid cells in the brain, provide acute and chronic surveillance of damage- and pathogen-associated signals as a part of the innate immune system[1]. Elevated expression of TREM2 gene is reported to ameliorate pathological phenotypes in AD models[24] These studies highlight that functional alterations of TREM2 due to mutation contribute to the development of neurodegenerative disorders, possibly by loss of function[25,26], and indicate that a better understanding of the role of TREM2 could provide new insights for drug discovery. We have developed a highly sensitive reporter cell model to monitor signal transduction from TREM2, in order to identify the TREM2 ligands on apoptotic and normal cultured cells and to search for other ligands in the brain that may be associated with increased incidence of AD. We suggest that other TREM2 signal-transducing ligands are present in the membranes of mouse cerebral cortex
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