Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy
Open accessAbstract
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. We used transgenic mice lacking endogenous Cx 3 cl 1 ( 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 105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. First, increased basal tau levels accompanied microglial activation in Cx 3 cl1 105Δ 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 105Δ 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 105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx 3 cr1 deletion), which likely contributes to the elevated tau pathology. Collectively, our data suggest that overexpression of only chemokine domain of CX 3 CL1 does not protect against tau pathology.
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Cx3cl1 expressed by neurons interacts with the microglial receptor Cx3cr1 and restricts microglia-mediated neuroinflammation.
“The further study discovered that Cx3cl1 expressed by neurons interacted with the microglial receptor Cx3cr1 and restricted microglia-mediated neuroinflammation.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [396]
Genetic ablation of Cx3cl1 or Cx3cr1 in mouse models of tauopathy enhances tau hyperphosphorylation, tau pathology, neuroinflammation, and cognitive deficits via the IL-1/p38 MAPK pathway.
“Genetic ablation of Cx3cl1396,397 or Cx3cr1389,398 in mouse models of tauopathy enhanced tau hyperphosphorylation, tau pathology, neuroinflammation, and cognitive deficits389,396–398 via IL-1/p38 MAPK pathway.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [396]
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- Authors
- Bemiller, S. M., Maphis, N. M., Formica, S. V., Wilson, G. N., Miller, C. M., Xu, G., Kokiko-Cochran, O. N., Kim, K.-W., Jung, S., Cannon, J. L., Crish, S. D., Cardona, A. E., Lamb, B. T., & Bhaskar, K.
- Affiliations
- Cleveland Clinic (US)
- University of New Mexico (US)
- Kent State University (US)
- Indiana University School of Medicine (US)
- Washington University in St. Louis (US)
- Weizmann Institute of Science (IL)
- Northeast Ohio Medical University (US)
- The University of Texas at San Antonio (US)
- Corresponding author
- Bhaskar, Kiran
- ORCID
- Venue
- Journal of Neuroinflammation
- Published
- 2018-09-25
- Volume
- 15
- Issue
- 1
- Pages
- 278-278
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC6154806
- OpenAlex
- W2893176204
- Cited by
- 24
- References
- 36
- Citations by year
- 2026: 2 · 2025: 4 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 3
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by-nc-nd)
- Funders
- American Health Assistance Foundation (AHAF0311)
- National Institute on Aging (F31AG050409-01A1, R01AG023012 and RF1AG051495)
- Indiana Clinical and Translational Sciences Institute (UL1TR001108)
- National Institute of Neurological Disorders and Stroke (R01NS047804, R01NS078501, R21NS077089, R21NS093442, R01NS083704)
- National Eye Institute (R01EY022358)
- U.S. Department of Defense (W81XWH-13 MRPRA-CSRA)
- National Institute of General Medical Sciences (SC1GM095426)
- Alzheimer's Association (NIRG-11-204995)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- fractalkine, CX3CR1, tauopathy, tau phosphorylation, microglial activation, neuroinflammation, lipopolysaccharide-induced neuroinflammation, spatial learning impairment, receptor internalization
- MeSH terms
- Animals, Antigens, Differentiation, Calcium-Binding Proteins, Cognition Disorders, Disease Models, Animal, Gene Expression Regulation, Lipopolysaccharides, Mice, Transgenic, Microfilament Proteins, Mutation, Cytokines, tau Proteins, Microglia, Maze Learning, Tauopathies, Mice, Chemokine CX3CL1
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