Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy

Shane M. Bemiller, Nicole M. Maphis, Shane V. Formica, Gina N. Wilson, Crystal M. Miller, Guixiang Xu, Olga N. Kokiko-Cochran, Ki Wook Kim, Steffen Jung, Judy L. Cannon, Samuel D. Crish, Astrid E. Cardona, Bruce T. Lamb, Kiran Bhaskar

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Background: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx 3 cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. Methods: We used transgenic mice lacking endogenous Cx 3 cl1 (Cx 3 cl1 -/-) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx 3 cl1 105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. Results: First, increased basal tau levels accompanied microglial activation in Cx 3 cl1 105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx 3 cl1 -/-, and hTau/Cx 3 cl1 105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx 3 cl1 105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx 3 cr1 deletion), which likely contributes to the elevated tau pathology. Conclusions: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.

Original languageEnglish (US)
Article number278
JournalJournal of Neuroinflammation
Volume15
Issue number1
DOIs
StatePublished - Sep 25 2018

Keywords

  • Alzheimer's disease
  • CXCL1
  • CXCR1
  • Microglia
  • Neuroinflammation
  • Tau
  • Tauopathies

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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    Bemiller, S. M., Maphis, N. M., Formica, S. V., Wilson, G. N., Miller, C. M., Xu, G., Kokiko-Cochran, O. N., Kim, K. W., Jung, S., Cannon, J. L., Crish, S. D., Cardona, A. E., Lamb, B. T., & Bhaskar, K. (2018). Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy. Journal of Neuroinflammation, 15(1), [278]. https://doi.org/10.1186/s12974-018-1310-6