The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E*

Background: Mutations in the triggering receptor on myeloid cells 2 (TREM2) are associated with several neurodegenerative diseases, including Alzheimer disease, but the relevant TREM2 ligand is unknown. Results: TREM2 binds to apolipoprotein E (ApoE). Conclusion: TREM2 is a cellular receptor for ApoE. Significance: Identification of ApoE as a TREM2 ligand helps explain the role of TREM2 role in neurodegenerative disorders. The triggering receptor expressed on myeloid cells 2 (TREM2) is an Ig-like V-type receptor expressed by populations of myeloid cells in the central nervous system and periphery. Loss-of-function mutations in TREM2 cause a progressive, fatal neurodegenerative disorder called Nasu-Hakola disease. In addition, a TREM2 R47H coding variant was recently identified as a risk factor for late-onset Alzheimer disease. TREM2 binds various polyanionic molecules but no specific protein ligands have been identified. Here we show that TREM2 specifically binds apolipoprotein E, a well established participant in Alzheimer disease. TREM2-Ig fusions efficiently precipitate ApoE from cerebrospinal fluid and serum. TREM2 also binds recombinant ApoE in solution and immobilized ApoE as detected by ELISA. Furthermore, the Alzheimer disease-associated R47H mutation, and other artificial mutations introduced in the same location, markedly reduced the affinity of TREM2 for ApoE. These findings reveal a link between two Alzheimer disease risk factors and may provide important clues to the pathogenesis of Nasu-Hakola disease and other neurodegenerative disorders.