Abstract
BackgroundFractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 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.MethodsWe used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1−/−) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy.ResultsFirst, increased basal tau levels accompanied microglial activation in Cx3cl1105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1−/−, and hTau/Cx3cl1105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology.ConclusionsCollectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
Highlights
Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function
Fractalkine chemokine (CX3CL1)-CX3CR1 signaling is regulated through direct neuron-microglia interaction, which acts to tether microglia until pathological activation, via an inflammatory influence, or through normal physiological activity, which disrupts this interaction through the cleavage of CX3CL1 [12, 13]
Converse to the protective anti-amyloid phenotype observed in Amyloid precursor protein presenilin-1 (APPPS1)/Fractalkine receptor (Cx3cr1)−/− mice, deletion of Cx3cr1 in hTau mice resulted in hyperphosphorylation and aggregation of tau, worsened cognitive function, and increased microglial inflammation [17]
Summary
Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We found that disrupting the CX3CL1-CX3CR1 signaling axis reduces Aβ burden with concomitant increases in pro-inflammatory IL-1 and heightened microglial activation in both APPPS1/ Cx3cr1−/− and APPPS1/Cx3cl1−/− transgenic mouse models of AD [18] This phenomenon was unaffected by the presence of soluble CX3CL1 [18]. Converse to the protective anti-amyloid phenotype observed in APPPS1/Cx3cr1−/− mice, deletion of Cx3cr in hTau mice resulted in hyperphosphorylation and aggregation of tau, worsened cognitive function, and increased microglial inflammation [17]. This effect was regulated via the same IL-1-p38 MAPK axis [17, 19]. The present study seeks to determine if genetically expressing only the soluble chemokine domain of CX3CL1 could prevent tau pathology in both chemical (LPS) and genetic (hTau) mouse models of tauopathy
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