The Alzheimer's disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are genetically linked to Alzheimer's disease. Here, we investigated whether human ApoE mediates signal transduction through human and murine TREM2 and sought to identify a TREM2-binding domain in human ApoE. Methods: To investigate cell signaling through TREM2, a cell line was used which expressed an NFAT-inducible beta-galactosidase reporter and human or murine TREM2, fused to CD8 transmembrane and CD3 zeta. intracellular signaling domains. ELISA-based binding assays were used to determine binding affinities of human ApoE isoforms to human TREM2 and to identify a TREM2-binding domain in ApoE. Results: ApoE was found to be an agonist to human TREM2 with EC50 in the low nM range, and to murine TREM2 with reduced potency. In the reporter cells, TREM2 expression was lower than in nontransgenic mouse brain. Human ApoE isoforms epsilon 2, epsilon 3, and epsilon 4 bound to human TREM2 with K-d in the low nM range. The binding was displaced by an ApoE-mimetic peptide (amino acids 130-149). Conclusions: An ApoE-mediated dose-dependent signal transduction through TREM2 in reporter cells was demonstrated, and a TREM2-binding region in ApoE was identified. The relevance of an ApoE-TREM2 receptor signaling pathway to Alzheimer's disease is discussed.