Opposing Effects of Membrane-Anchored CX3CL1 on Amyloid and Tau Pathologies via the p38 MAPK Pathway
Open accessAbstract
Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD—extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)—remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the “frustrated phagocytosis” concept and suggest that neuronal–microglial communication link the two central AD pathologies.
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Accumulating evidence shows that microglia and monocytes play distinct roles in AD pathogenesis, thus implicating both the central and peripheral immune response in long-term outcome.
“Finally, accumulating evidence shows that microglia and monocytes play distinct roles in AD pathogenesis (116–119), thus implicating both the central and peripheral immune response in long-term outcome.”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [118]
The Introduction (page unavailable) says accumulating evidence implicates microglia-mediated neuroinflammation in AD pathogenesis, and the Discussion reports effects of altered microglial activity in APPPS1 mice. The paper does not establish distinct roles for microglia and monocytes or connect peripheral immune responses to long-term outcome; its mention of monocyte chemotactic protein 1 is not a comparison of the two cell types. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDeletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments.
“Deletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition [130–132] but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments [132–137] (Fig. 1).”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [133]
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 [397]
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 [397]
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References 40 · Cited by 123
- Authors
- Lee, S., Xu, G., Jay, T. R., Bhatta, S., Kim, K.-W., Jung, S., Landreth, G. E., Ransohoff, R. M., & Lamb, B. T.
- Affiliations
- Cleveland Clinic (US)
- Weizmann Institute of Science (IL)
- Case Western Reserve University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-09-10
- Volume
- 34
- Issue
- 37
- Pages
- 12538-12546
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4160782
- OpenAlex
- W2117478398
- Cited by
- 123
- References
- 40
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 7 · 2023: 13 · 2022: 20 · 2021: 8 · 2020: 9 · 2019: 10 · 2018: 14 · 2017: 9 · 2016: 9 · 2015: 11 · 2014: 1
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Multiple Sclerosis Society
- National Institute on Aging (R01AG023012, AG023012)
- National Institute of General Medical Sciences (T32GM007250)
- National Institute of Neurological Disorders and Stroke (NS067431, NS047804, T32NS067431, R01NS074804, F30NS068003)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- fractalkine, CX3CR1, Alzheimer's disease, amyloid-beta deposition, tau hyperphosphorylation, microglia, p38 MAPK, APP/PS1 mice, microglial phagocytosis, frustrated phagocytosis, neuroinflammation, microglial activation
- MeSH terms
- Alzheimer Disease, Animals, Cell Membrane, Cells, Cultured, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Peptides, tau Proteins, Microglia, MAP Kinase Signaling System, p38 Mitogen-Activated Protein Kinases, Mice, Chemokine CXCL1
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