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CX3CR1 Protein Signaling Modulates Microglial Activation and Protects against Plaque-independent Cognitive Deficits in a Mouse Model of Alzheimer Disease
Open accessAbstract
Aberrant microglial activation has been proposed to contribute to the cognitive decline in Alzheimer disease (AD), but the underlying molecular mechanisms remain enigmatic. Fractalkine signaling, a pathway mediating the communication between microglia and neurons, is deficient in AD brains and down-regulated by amyloid-β. Although fractalkine receptor (CX3CR1) on microglia was found to regulate plaque load, no functional effects have been reported. Our study demonstrates that CX3CR1 deficiency worsens the AD-related neuronal and behavioral deficits. The effects were associated with cytokine production but not with plaque deposition. Ablation of CX3CR1 in mice overexpressing human amyloid precursor protein enhanced Tau pathology and exacerbated the depletion of calbindin in the dentate gyrus. The levels of calbindin in the dentate gyrus correlated negatively with those of tumor necrosis factor α and interleukin 6, suggesting neurotoxic effects of inflammatory factors. Functionally, removing CX3CR1 in human amyloid precursor protein mice worsened the memory retention in passive avoidance and novel object recognition tests, and their memory loss in the novel object recognition test is associated with high levels of interleukin 6. Our findings identify CX3CR1 as a key microglial pathway in protecting against AD-related cognitive deficits that are associated with aberrant microglial activation and elevated inflammatory cytokines.
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“However, such complete deletion has also been associated with worsening memory deficits and tau pathology (28–31).”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [29]
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“Postmortem analyses show modest reductions of CX3CR1 and markedly lower levels of CX3CL1 in the hippocampus of AD brains compared with age-matched nondemented controls [178].”
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Metadata
- Authors
- Cho, S.-H., Sun, B., Zhou, Y., Kauppinen, T. M., Halabisky, B., Wes, P., Ransohoff, R. M., & Gan, L.
- Affiliations
- Gladstone Institutes (US)
- University of California, San Francisco (US)
- Bristol-Myers Squibb (United States) (US)
- Cleveland Clinic (US)
- Corresponding author
- Gan, Li
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 286
- Issue
- 37
- Pages
- 32713-32722
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3173153
- OpenAlex
- W2148721608
- Cited by
- 268
- References
- 52
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 14 · 2023: 20 · 2022: 15 · 2021: 14 · 2020: 16 · 2019: 20 · 2018: 18 · 2017: 17 · 2016: 18 · 2015: 28 · 2014: 27 · 2013: 22 · 2012: 14
- FWCI
- 11.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1c06rr018928-01)
- University of California, San Diego
- National Institute on Aging (R01AG030207)
- National Cancer Institute (CO6 RRO18928)
- National Institute of Neurological Disorders and Stroke (P30NS065780)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- CX3CR1, microglial activation, Alzheimer's disease, cognitive impairment, amyloid precursor protein, tau pathology, calbindin, dentate gyrus, neuroinflammation, interleukin-6, TNF-α, memory impairment, novel object recognition, passive avoidance
- MeSH terms
- CX3C Chemokine Receptor 1, Alzheimer Disease, Animals, Cognition Disorders, Disease Models, Animal, Humans, Nerve Tissue Proteins, Signal Transduction, Cytokines, Amyloid beta-Protein Precursor, Microglia, Mice, Knockout, Dentate Gyrus, Receptors, Chemokine, Mice, Calbindins, S100 Calcium Binding Protein G
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