Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity

J Exp Med. 2017 Apr 3;214(4):1081-1092. doi: 10.1084/jem.20162011. Epub 2017 Mar 15.


Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aβ levels and Aβ half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aβ clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aβ metabolism and defining a potential new therapeutic target in AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / etiology
  • Amyloid beta-Peptides / analysis*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / physiology
  • Animals
  • Benzoates / pharmacology
  • Brain / metabolism*
  • Macrophage-1 Antigen / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Microglia / physiology*
  • Proteolysis
  • Thiohydantoins / pharmacology


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Benzoates
  • Macrophage-1 Antigen
  • Thiohydantoins
  • leukadherin-1