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

ABSTRACT: BACKGROUND:Fractalkine (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. METHODS:We 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 Cx3cl1105? 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 Cx3cl1105? mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1-/-, and hTau/Cx3cl1105? mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105? mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 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.

SUBMITTER: Bemiller SM

PROVIDER: S-EPMC6154806 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Genetically enhancing the expression of chemokine domain of CX<sub>3</sub>CL1 fails to prevent tau pathology in mouse models of tauopathy.

Bemiller Shane M SM Maphis Nicole M NM Formica Shane V SV Wilson Gina N GN Miller Crystal M CM Xu Guixiang G Kokiko-Cochran Olga N ON Kim Ki-Wook KW Jung Steffen S Cannon Judy L JL Crish Samuel D SD Cardona Astrid E AE Lamb Bruce T BT Bhaskar Kiran K

Journal of neuroinflammation 20180925 1

<h4>Background</h4>Fractalkine (CX<sub>3</sub>CL1) and its receptor (CX<sub>3</sub>CR1) play an important role in regulating microglial function. We have previously shown that Cx<sub>3</sub>cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX<sub>3</sub>CL1 is essential in regulating neuronal tau pathology.<h4>Methods</h4>We used transgenic mice lacking endogenous Cx<sub>3</sub>cl1 (Cx<sub>3</sub>cl1<sup>- ...[more]

PMID: 30253780

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

Publications

Genetically enhancing the expression of chemokine domain of CX<sub>3</sub>CL1 fails to prevent tau pathology in mouse models of tauopathy.

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