CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease

J Biol Chem. 2011 Sep 16;286(37):32713-22. doi: 10.1074/jbc.M111.254268. Epub 2011 Jul 19.


Aberrant microglial activation has been proposed to contribute to the cognitive decline in Alzheimer disease (AD), but the underlying molecular mechanisms remain enigmatic. Fractalkine signaling, a pathway mediating the communication between microglia and neurons, is deficient in AD brains and down-regulated by amyloid-β. Although fractalkine receptor (CX3CR1) on microglia was found to regulate plaque load, no functional effects have been reported. Our study demonstrates that CX3CR1 deficiency worsens the AD-related neuronal and behavioral deficits. The effects were associated with cytokine production but not with plaque deposition. Ablation of CX3CR1 in mice overexpressing human amyloid precursor protein enhanced Tau pathology and exacerbated the depletion of calbindin in the dentate gyrus. The levels of calbindin in the dentate gyrus correlated negatively with those of tumor necrosis factor α and interleukin 6, suggesting neurotoxic effects of inflammatory factors. Functionally, removing CX3CR1 in human amyloid precursor protein mice worsened the memory retention in passive avoidance and novel object recognition tests, and their memory loss in the novel object recognition test is associated with high levels of interleukin 6. Our findings identify CX3CR1 as a key microglial pathway in protecting against AD-related cognitive deficits that are associated with aberrant microglial activation and elevated inflammatory cytokines.

Publication types

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

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • CX3C Chemokine Receptor 1
  • Calbindins
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism*
  • Cognition Disorders / pathology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dentate Gyrus / metabolism
  • Dentate Gyrus / pathology
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Knockout
  • Microglia / metabolism*
  • Microglia / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • S100 Calcium Binding Protein G / genetics
  • S100 Calcium Binding Protein G / metabolism
  • Signal Transduction*


  • Amyloid beta-Protein Precursor
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, human
  • Calbindins
  • Cx3cr1 protein, mouse
  • Cytokines
  • Nerve Tissue Proteins
  • Receptors, Chemokine
  • S100 Calcium Binding Protein G