title: The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E.
abstract: 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.
authors.affiliation: From the Department of Immunobiology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida 33458 cbailey@scripps.edu.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Bailey
authors.affiliation: From the Department of Immunobiology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: DeVaux
authors.affiliation: From the Department of Immunobiology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
mesh_terms: D001057:Apolipoproteins E / Q000134:cerebrospinal fluid / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D019169:Jurkat Cells; D050356:Lipid Metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer disease; Nasu-Hakola disease; PLOSL; TREM2; apolipoprotein E (ApoE); genetic polymorphism; high-density lipoprotein (HDL); myeloid cell; neurodegenerative disease