Genetically enhancing the expression of chemokine domain of CXCL1 fails to prevent tau pathology in mouse models of tauopathy.

Background: Fractalkine (CXCL1) and its receptor (CXCR1) play an important role in regulating microglial function. We have previously shown that Cxcr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CXCL1 is essential in regulating neuronal tau pathology.

Methods: We used transgenic mice lacking endogenous Cxcl1 (Cxcl1) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CXCL1 (referred to as Cxcl1 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 Cxcl1 mice compared to control groups. Second, increased CD45 and F4/80 neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cxcl1, and hTau/Cxcl1 mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CXCR1 was reduced in Cxcl1 mice, suggesting enhanced fractalkine receptor internalization (mimicking Cxcr1 deletion), which likely contributes to the elevated tau pathology.

Conclusions: Collectively, our data suggest that overexpression of only chemokine domain of CXCL1 does not protect against tau pathology.