title: TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.
abstract: Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity. Trem2 knockout microglia showed reduced internalization of LDL and CLU. β-amyloid (Aβ) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of Aβ-lipoprotein complexes was reduced in macrophages from human subjects carrying a TREM2 AD variant. These data link three genetic risk factors for AD and reveal a possible mechanism by which mutant TREM2 increases risk of AD. VIDEO ABSTRACT.
authors.affiliation: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Felix L
authors.initials: FL
authors.lastname: Yeh
authors.affiliation: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Proteomics and Biological Resources, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Tom
authors.affiliation: Department of Proteomics and Biological Resources, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: gonzalez.lino@gene.com.
authors.forename: Lino C
authors.initials: LC
authors.lastname: Gonzalez
authors.affiliation: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: sheng.morgan@gene.com.
authors.forename: Morgan
authors.initials: M
authors.lastname: Sheng
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001053:Apolipoproteins / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism*; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D001053:Apolipoproteins; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human