title: Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2.
abstract: BACKGROUND
  Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer's disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer's disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer's disease, we tested whether loss of one functional trem2 allele would affect Aβ plaque deposition or the microglial response to Aβ pathology in APPPS1-21 mice.
  
  
  RESULTS
  There was no significant difference in Aβ deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2+/- vs. TREM2+/+ mice.
  
  
  CONCLUSIONS
  Loss of a single copy of trem2 had no effect on Aβ pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aβ deposition but that a 50% decrease inTREM2 expression does not affect Aβ plaque burden.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Ulrich
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Finn
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wang
authors.forename: Alice
authors.initials: A
authors.lastname: Shen
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mahan
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.forename: Laura
authors.initials: L
authors.lastname: Piccio
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA. holtzman@neuro.wustl.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics*
chemical_list: D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D053764:Presenilin-1; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse