Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy
Open accessAbstract
Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation. Experiments with fractalkine receptor null mice suggest that fractalkine signaling diminishes tau pathology, but exacerbates amyloid pathology. Consistent with this outcome, we report here that soluble fractalkine overexpression using adeno-associated viral vectors significantly reduced tau pathology in the rTg4510 mouse model of tau deposition. Furthermore, this treatment reduced microglial activation and appeared to prevent neurodegeneration normally found in this model. However, in contrast to studies with fractalkine receptor null mice, parallel studies in an APP/PS1 model found no effect of increased fractalkine signaling on amyloid deposition. These data argue that agonism at fractalkine receptors might be an excellent target for therapeutic intervention in tauopathies, including those associated with amyloid deposition.
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Tau pathology reduced by inhibiting microglial activation via CX3CL1 overexpression or anti-inflammatory drugs.
“tau pathology was reduced by inhibiting microglial activation via overexpression of CX3CL1, a chemokine released by neurons that binds to microglial-expressed CX3CR1 [240] or by administration of anti-inflammatory drugs [113]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [240]
In tauopathies, microglia first sense and clear tau, but dysregulation of Cx3cr1 and Trem2 pathways leads to dysregulated host defense and neuroinflammatory damage.
“Microglia first sense and clear tau in an attempt to protect from tau toxicity, but dysregulation of microglial sensing and housekeeping pathways, such as the Cx3cr1 and Trem2 pathways, lead to dysregulation of the host-defense pathway, resulting in a neuroinflammatory response gone awry, causing neuronal damage and loss55–57.”
From Microglia in neurodegeneration (2018) · cites this paper as [56]
Overexpressing a soluble form of CX3CL1, the ligand for CX3CR1, reduces microglial cell activation and tau pathology in rTg4510 mice.
“overexpressing a soluble form of CX3CL1, the ligand for CX3CR1, reduces microglial cell activation and tau pathology in rTg4510 mice [G]64.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [64]
Overexpression of soluble CX3CL1 reduces microglial activation and neuronal loss in rTg4510 mice.
“Similarly, overexpression of soluble CX3CL1 reduces microglial activation and neuronal loss in rTg4510 mice64.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [64]
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- Authors
- Nash, K. R., Lee, D. C., Hunt, J. B., Morganti, J. M., Selenica, M.-L., Moran, P., Reid, P., Brownlow, M., Guang-Yu Yang, C., Savalia, M., Gemma, C., Bickford, P. C., Gordon, M. N., & Morgan, D.
- Affiliations
- University of South Florida (US)
- University of California, San Francisco (US)
- University of Washington (US)
- Corresponding author
- Nash, Kevin R.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 34
- Issue
- 6
- Pages
- 1540-1548
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC8970215
- OpenAlex
- W2144997087
- Cited by
- 108
- References
- 50
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 8 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 11 · 2018: 8 · 2017: 7 · 2016: 9 · 2015: 10 · 2014: 9 · 2013: 7
- FWCI
- 8.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH/NIA (R01 AG025509, NIH NS76308, NIH AG15470)
- 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, tau pathology, tauopathy, Alzheimer's disease, microglial activation, neuroinflammation, adeno-associated virus vectors, amyloid deposition, APP/PS1 mice, neurodegeneration, chemokines
- MeSH terms
- Animals, Disease Models, Animal, Gene Expression Regulation, Mice, Transgenic, tau Proteins, Tauopathies, Mice, Chemokine CX3CL1
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