Microglial CX3CR1 production increases in Alzheimer's disease and is regulated by noradrenaline

Glia. 2021 Jan;69(1):73-90. doi: 10.1002/glia.23885. Epub 2020 Jul 14.


The loss of noradrenergic neurons and subsequent reduction of brain noradrenaline (NA) levels are associated with the progression of Alzheimer's disease (AD). This seems to be due mainly to the ability of NA to reduce the activation of microglial cells. We previously observed that NA induces the production of the chemokine Fractalkine/CX3CL1 in neurons. The activation of microglial CX3CR1, sole receptor for CX3CL1, reduces the activation of microglia, which is known to largely contribute to the neuronal damage characteristic of AD. Therefore, alterations of CX3CR1 production in microglia could translate into the enhancement or inhibition of CX3CL1 anti-inflammatory effects. In order to determine if microglial CX3CR1 production is altered in AD and if NA can control it, CX3CR1 expression and synthesis were analyzed in 5xFAD mice and human AD brain samples. In addition, the effects of NA and its reuptake inhibitor reboxetine were analyzed in microglial cultures and mice respectively. Our results indicate that in AD CX3CR1 production is increased in the brain cortex and that reboxetine administration further increases it and enhances microglial reactivity toward amyloid beta plaques. However, direct administration of NA to primary rat microglia or human HMC3 cells inhibits CX3CR1 production, suggesting that microglia responses to NA may be altered in the absence of CX3CL1-producing neurons or other nonmicroglial external factors.

Keywords: (5-7) CX3CR1; 5xFAD; Alzheimer's disease; CX3CL1; Fractalkine; noradrenaline; reboxetine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Amyloid beta-Peptides
  • Animals
  • CX3C Chemokine Receptor 1 / genetics
  • Mice
  • Microglia*
  • Norepinephrine
  • Rats
  • Reboxetine


  • Amyloid beta-Peptides
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, rat
  • Cx3cr1 protein, mouse
  • Reboxetine
  • Norepinephrine