Genetically enhancing the expression of chemokine domain of CX(3)CL1 fails to prevent tau pathology in mouse models of tauopathy

Background: Fractalkine (CX(3)CL1) and its receptor (CX(3)CR1) 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 CX(3)CL1 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 CX(3)CL1 (referred to as Cx(3)cl1(105 Delta) 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(105 Delta) 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(105 Delta) mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX(3)CR1 was reduced in Cx(3)cl1(105 Delta) 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 CX(3)CL1 does not protect against tau pathology.