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Regulation of Tau Pathology by the Microglial Fractalkine Receptor
Open accessAbstract
Aggregates of the hyperphosphorylated microtubule-associated protein tau (MAPT) are an invariant neuropathological feature of tauopathies. Here, we show that microglial neuroinflammation promotes MAPT phosphorylation and aggregation. First, lipopolysaccharide-induced microglial activation promotes hyperphosphorylation of endogenous mouse MAPT in nontransgenic mice that is further enhanced in mice lacking the microglial-specific fractalkine receptor (CX3CR1) and is dependent upon functional toll-like receptor 4 and interleukin-1 (IL-1) receptors. Second, humanized MAPT transgenic mice lacking CX3CR1 exhibited enhanced MAPT phosphorylation and aggregation as well as behavioral impairments that correlated with increased levels of active p38 MAPK. Third, in vitro experiments demonstrate that microglial activation elevates the level of active p38 MAPK and enhances MAPT hyperphosphorylation within neurons that can be blocked by administration of an interleukin-1 receptor antagonist and a specific p38 MAPK inhibitor. Taken together, our results suggest that CX3CR1 and IL-1/p38 MAPK may serve as novel therapeutic targets for human tauopathies.
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“Notably, we observed elevated levels of active (phosphorylated) p38α MAPK, but not GSK3β or regulators (p35/p25) of Cdk5, correlating with increased tau phosphorylation in the hippocampus of hTau mice deficient for the chemokine receptor CX3CR1 [22].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [22]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The p38α-mediated cytokine overproduction in microglia has been linked to inflammation-induced neurotoxicity in a variety of mouse models [22, 27–33].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [22]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We have demonstrated recently that activated microglia induced tau hyperphosphorylation via activation of the p38α MAPK signaling pathway in the hTau mouse model of tauopathy [22, 23].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [22]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As reported previously [22], exchange of 25% of the neuronal supernatant with Cx3cr1 –/– microglia CM led to an increase in tau phosphorylation on S199/S202 (AT8) and T231 (AT180) sites (Fig. 1d, e).”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [22]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, hyperphosphorylation of tau in this model was mediated by upregulation of p38α the MAPK pathway, but not GSK3β or CDK5 pathways [22].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [22]
Experimental — accuracy not yet measured
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In the citing paper
“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 [116]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Neuroinflammation is an early feature of pathophysiology in mouse models of tauopathy, where inflammatory changes precede the accumulation of aggregated tau (Yoshiyama et al., 2007) and pro-inflammatory molecules increase tau hyperphosphorylation and aggregation (Bhaskar et al., 2010).”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Bhaskar et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“As reported previously [22], a single injection of LPS led to AT8 and AT180 site tau phosphorylation in nontransgenic mice (Fig. 4b–d).”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [22]
The cited source says what the claim attributes to it.
In the citing paper
“Our previous study suggested that enhancement of microglia-specific neuroinflammation via genetic deficiency of Cx3cr1 resulted in accelerated tau pathology and cognitive impairment in an hTau mouse model of tauopathy [22].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [22]
The cited source says what the claim attributes to it.
In the citing paper
“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 [28]
The cited source says what the claim attributes to it.
In the citing paper
“Similarly, deficiency of Cx3cr1 reduced amyloid deposition in two different APP models but aggravated tau hyperphosphorylation in hTau mice [65, 66].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [65]
In the citing paper
“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 [137]
In the citing paper
“Bhaskar et al. reported that microglia activation induces tau hyperphosphorylation via the IL-1β/p38α MAPK pathway in vitro and in vivo [135, 137].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [137]
In the citing paper
“As mentioned above, p38α MAPK is a key kinase involved in microglia-induced neuroinflammation leading to tau pathology [135, 137], and this kinase can also directly regulate tau phosphorylation [39].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [137]
In the citing paper
“the exacerbation of tau pathology in Cx3cr1 knockout mice was blocked with IL-1 antagonists (Bhaskar et al., 2010; Maphis et al., 2015)”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Bhaskar et al., 2010
In the citing paper
“Deleting the microglial protein Cx3cr1 in transgenic tau models showed that genetically enhanced microglial activation accelerated the onset and progression of tau pathology (Bhaskar et al., 2010; Maphis et al., 2015).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Bhaskar et al., 2010
In the citing paper
“However, pretreating the neurons with an IL-1R antagonist attenuated the effects of CX3CR1−/− conditioned media”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [136]
In the citing paper
“Additionally, p38-MAPK levels were significantly increased in CX3CR1 deficient htau mice, though no changes were detected in GSK-3β or p25.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [136]
In the citing paper
“thereby suggesting microglial-derived IL-1β promotes tau phosphorylation via p38-MAPK in neurons [136].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [136]
In the citing paper
“Genetic deletion of CX3CR1 in mice expressing human tau under its endogenous promoter (htau mice) led to substantially increased microglial activation indicated by CD68 staining as well as elevated levels of p-tau and insoluble tau aggregates [136].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [136]
In the citing paper
“The interaction between IL-1β driven neuroinflammation and neuronal tau hyperphosphorylation may be partially regulated by the microglial-specific fractalkine receptor (CX3CR1).”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [136]
In the citing paper
“However, it should be noted that IL-1β is not sufficient to cause neurotoxicity or neurodegeneration in the absence of tau [136, 138].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [136]
In the citing paper
“the authors placed conditioned media from CX3CR1−/− microglia on wildtype neurons and observed comparable increases in p38-MAPK and p-tau.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [136]
In the citing paper
“Endotoxin promotes amyloid β and tau aggregation and neuropathology”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [69]
In the citing paper
“and systemic endotoxin precipitates brain pathology in mice expressing prions [74], APP variants [33] or TAU variants [69] or mice with α-synuclein injected in the brain [46].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [69]
In the citing paper
“Endotoxin may also promote the production or aggregation of amyloid β [66–68], tau [68, 69] and α-synuclein [70, 71].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [69]
In the citing paper
“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 [55]
In the citing paper
“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 [389]
In the citing paper
“The deficiency of the CX3CR1 enhanced tau phosphorylation and aggregation and memory impairment in a transgenic mouse model of tauopathy in which the WT human MAPT gene replaced the endogenous mouse Mapt gene (hTau mice).389”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [389]
In the citing paper
“In patients with MAPT mutations, neuroinflammation may be triggered by the misfolding of mutant tau and contribute to its hyperphosphorylation and aggregation[4,14,16], while in C9orf72 and GRN cases, neuroinflammation could be triggered by dipeptide repeats or progranulin haploinsufficiency in advance of the large TDP-43 aggregates[14,17].”
From In vivo PET imaging of neuroinflammation in familial frontotemporal dementia (2021) · cites this paper as [16]
In the citing paper
“First, the proinflammatory cytokines TNFα, IL1 β, and IL6 have been shown to promote tau phosphorylation in neurons (Bhaskar et al., 2010; Kitazawa et al., 2011; Quintanilla et al., 2004).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Bhaskar et al., 2010
In the citing paper
“deleting the microglial cell-expressed homeostatic gene CX3C chemokine receptor 1(Cx3cr1) in htau mice [G] leads to amplified microglial activation and enhanced tau hyperphosphorylation/aggregation62,63”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [62]
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Citations
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In vivo imaging of microglial activation with [11C](R)‐PK11195 PET in progressive supranuclear palsy
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“First, activated microglia are found in the postmortem brain tissues of various human tauopathies including Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy and corticobasal degeneration (Gebicke-Haerter, 2001; Gerhard et al., 2006; Ishizawa and Dickson, 2001).”
Minocycline reduces the development of abnormal tau species in models of Alzheimer's disease
Noble, W., Garwood, C., Stephenson, J., Kinsey, A. M., Hanger, D., & Anderton, B. (2009) · The FASEB Journal · doi:10.1096/fj.08-113795 · Cited by 123 · cited 1×
“This is consistent with several other recent observations in the hTau mice (Kelleher et al., 2007; Noble et al., 2009) as well as other mouse model of tauopathies (Kitazawa et al.”
Varvel, N. H., Bhaskar, K., Kounnas, M. Z., Wagner, S. L., Yang, Y., Lamb, B. T., & Herrup, K. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39716 · Cited by 122
Self-citationHauss‐Wegrzyniak, B., Lukovic, L., Bigaud, M., & Stoeckel, M. E. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00227-3 · Cited by 108 · cited 1×
“LPS has also been utilized asmodel to examine the role neuroinflammation via either peripheral administration in systemic inflammation or direct administration into the brain (Hauss-Wegrzyniak et al., 1998).”
Kinase activities increase during the development of tauopathy in htau mice
Kelleher, I., Garwood, C., Hanger, D. P., Anderton, B. H., & Noble, W. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04930.x · Cited by 78
Jiménez‐Andrade, J. M., Peters, C. M., Mejia, N. A., Ghilardi, J. R., Kuskowski, M. A., & Mantyh, P. W. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.06.043 · Cited by 78 · cited 1×
“To quantify the density of CD68-immunoreactive cells/structures, we referred earlier methods (Jimenez-Andrade et al., 2006) with slight modification.”
Emerging roles for telomerase in neuronal development and apoptosis
Mattson, M. P., & Klapper, W. (2001) · Journal of Neuroscience Research · doi:10.1002/1097-4547(20010101)63:1 · Cited by 76
Astrocytic nitric oxide triggers tau hyperphosphorylation in hippocampal neurons.
Saez, T. E., Pehar, M., Vargas, M. R., Barbeito, L., & Maccioni, R. B. (2004) · PubMed · Cited by 67
Masocha, W. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.06.022 · Cited by 65
HARTZLER, A., ZHU, X., SIEDLAK, S., CASTELLANI, R., AVILA, J., PERRY, G., & SMITH, M. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00029-5 · Cited by 43 · cited 2×
“Several different studies have provided evidence that p38 MAPK is one of the MAPT kinases that links neuroinflammation and MAPT phosphorylation in tauopathies (Hartzler et al., 2002; Hensley et al., 1999; Sun et al., 2003).”
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Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253
“[175] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT.”
BackgroundSelf-citationDifferential Roles of M1 and M2 Microglia in Neurodegenerative Diseases
Tang, Y., & Le, W. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-9070-5 · Cited by 2,190
“Enhanced pro-inflammatory activation ofmicroglia by disruption of CX3CR1, an anti-inflammatory CX3CL1 receptor, accelerates tangle formation [120].”
BackgroundMicroglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935
How neuroinflammation contributes to neurodegeneration
Ransohoff, R. M. (2016) · Science · doi:10.1126/science.aag2590 · Cited by 1,967
Self-citationMicroglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710
Metadata
- Authors
- Bhaskar, K., Konerth, M., Kokiko-Cochran, O. N., Cardona, A., Ransohoff, R. M., & Lamb, B. T.
- Affiliations
- Cleveland Clinic (US)
- Corresponding author
- Lamb, Bruce T.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 68
- Issue
- 1
- Pages
- 19-31
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2950825
- OpenAlex
- W2153206087
- Cited by
- 639
- References
- 49
- Citations by year
- 2026: 31 · 2025: 36 · 2024: 36 · 2023: 55 · 2022: 69 · 2021: 50 · 2020: 43 · 2019: 51 · 2018: 48 · 2017: 44 · 2016: 28 · 2015: 38 · 2014: 38 · 2013: 29 · 2012: 20
- FWCI
- 15.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1020 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Dana Foundation
- National Multiple Sclerosis Society
- CurePSP
- Alzheimer's Association
- National Institutes of Health (AG023012)
- American Health Assistance Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- tau hyperphosphorylation, tau aggregation, tauopathy, microglial activation, neuroinflammation, TLR4, interleukin-1 receptor, p38 MAPK, lipopolysaccharide, therapeutic target
- MeSH terms
- CX3C Chemokine Receptor 1, CD68 Molecule, Analysis of Variance, Animals, Animals, Newborn, Cell Count, Cells, Cultured, Disease Models, Animal, Enzyme Inhibitors, Gene Expression Regulation, Humans, Imidazoles, Lipopolysaccharides, Mice, Inbred C57BL, Models, Biological, Neurons, Phosphorylation, Pyridines, Time Factors, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Silver Staining, tau Proteins, Culture Media, Conditioned, Receptors, Interleukin-1, Microglia, Mice, Knockout, Statistics, Nonparametric, Maze Learning, Coculture Techniques, Receptors, Chemokine, Tauopathies, p38 Mitogen-Activated Protein Kinases, Toll-Like Receptor 4, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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