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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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Publications

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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Project description:Alzheimer's disease (AD), the most common tauopathy, is an age-dependent, progressive neurodegenerative disease. Epidemiological studies implicate the role of genetic background in the onset and progression of AD. Despite mutations in familial AD, several risk factors have been implicated in sporadic AD, of which the onset is unknown. In AD, there is a sequential and hierarchical spread of tau pathology to other brain areas. Studies have strived to understand the factors that influence this characteristic spread. Using transgenic rat models with different genetic backgrounds, we reported that the genetic background may influence the manifestation of neurofibrillary pathology. In this study we investigated whether genetic background has an influence in the spread of tau pathology, using hippocampal inoculations of insoluble tau from AD brains in rodent models of tauopathy with either a spontaneously hypertensive (SHR72) or Wistar-Kyoto (WKY72) genetic background. We observed that insoluble tau from human AD induced AT8-positive neurofibrillary structures in the hippocampus of both lines. However, there was no significant difference in the amount of neurofibrillary structures, but the extent of spread was prominent in the W72 line. On the other hand, we observed significantly higher levels of AT8-positive structures in the parietal and frontal cortical areas in W72 when compared to SHR72. Interestingly, we also observed that the microglia in these brain areas in W72 were predominantly phagocytic in morphology (62.4% in parietal and 47.3% in frontal), while in SHR72 the microglia were either reactive or ramified (67.2% in parietal and 84.7% in frontal). The microglia in the hippocampus and occipital cortex in both lines were reactive or ramified structures. Factors such as gender or age are not responsible for the differences observed in these animals. Put together, our results, for the first time, show that the immune response modulating genetic variability is one of the factors that influences the propagation of tau neurofibrillary pathology.

Dataset Information

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.

Similar Datasets

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