title: Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation.
abstract: BACKGROUND
  TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial.
  
  
  METHODS
  We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes.
  
  
  RESULTS
  We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells.
  
  
  CONCLUSIONS
  Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Wilbur
authors: W
authors: Song
authors: Department of Neurology, Harvard Medical School, and Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Basavaraj
authors: B
authors: Hooli
authors: Department of Neurology, Harvard Medical School, and Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Kristina
authors: K
authors: Mullin
authors: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors: Sheng Chih
authors: SC
authors: Jin
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Marina
authors: M
authors: Cella
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Tyler K
authors: TK
authors: Ulland
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Yaming
authors: Y
authors: Wang
authors: Department of Neurology, Harvard Medical School, and Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA. Electronic address: tanzi@helix.mgh.harvard.edu.
authors: Rudolph E
authors: RE
authors: Tanzi
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mcolonna@pathology.wustl.edu.
authors: Marco
authors: M
authors: Colonna
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D005190:Family; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D016015:Logistic Models; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism*
chemical_list: D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer's disease; HDL; LDL; Lipoprotein; Microglia; Monocyte; TREM2