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Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway.

Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD--extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)--remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the "frustrated phagocytosis" concept and suggest that neuronal-microglial communication link the two central AD pathologies.

Pubmed ID: 25209291 RIS Download

Mesh terms: Alzheimer Disease | Amyloid beta-Peptides | Animals | Cell Membrane | Cells, Cultured | Chemokine CXCL1 | Female | MAP Kinase Signaling System | Male | Mice | Mice, Inbred C57BL | Mice, Transgenic | Microglia | p38 Mitogen-Activated Protein Kinases | tau Proteins

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS074804
  • Agency: NIA NIH HHS, Id: AG023012
  • Agency: NINDS NIH HHS, Id: NS067431
  • Agency: NINDS NIH HHS, Id: NS047804
  • Agency: NINDS NIH HHS, Id: F30 NS068003
  • Agency: NIA NIH HHS, Id: R01 AG023012
  • Agency: NINDS NIH HHS, Id: T32 NS067431
  • Agency: NIGMS NIH HHS, Id: T32 GM007250

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Integrated Animals

Integrated Animals is a virtual database currently indexing available animal strains and mutants from: AGSC (Ambystoma), BCBC (mice), BDSC (flies), CWRU Cystic Fibrosis Mouse Models (mice), DGGR (flies), FlyBase (flies), IMSR (mice), MGI (mice), MMRRC (mice), NSRRC (pig), NXR (Xenopus), RGD (rats), Sperm Stem Cell Libraries for Biological Research (rats), Tetrahymena Stock Center (Tetrahymena), WormBase (worms), XGSC (Xiphophorus), ZFIN (zebrafish), and ZIRC (zebrafish).

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