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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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“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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Cites
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
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“Finally, CX3CR1 / mice crossed with mice overexpressing hTau have increased hyperphosphorylated tau and increased toxicity, likely related to the increase p38 and IL-1 (Bhaskar et al., 2010) expression.”
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Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
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Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer’s Disease
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BackgroundMethodInfluentialThe neuropathology and cerebrovascular mechanisms of dementia
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“These pathologic markers positively correlate with neuronal degeneration, neuroinflammation, microglia activation, BBB dysfunction, and cognitive decline.(27,28) Furthermore, NFT pathology in AD develops in three stages: transentorhinal, limbic, and isocortical, which is the basis of the Braak and Braak staging system…”
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Practical considerations for choosing a mouse model of Alzheimer’s disease
Jankowsky, J. L., & Zheng, H. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0231-7 · Cited by 449
“Disparities between tau transgenics and the htau model are also observed, most notably in the extent of neurodegeneration, gliosis, and cognitive decline which are quite limited and/or absent even in aged htau animals [39, 40, 81], but see [38, 42].”
BackgroundAutophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications
Uddin, M. S., Stachowiak, A., Mamun, A. A., Tzvetkov, N. T., Takeda, S., Atanasov, A. G., Bergantin, L. B., Abdel-Daim, M. M., & Stankiewicz, A. M. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00004 · Cited by 395
“Finally, Mapt deficiency reduces neuroinflammation (Maphis et al., 2015), while neuroinflammation in turn induces Mapt phosphorylation (Bhaskar et al., 2010).”
BackgroundGlial contributions to neurodegeneration in tauopathies
Leyns, C. E. G., & Holtzman, D. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0192-x · Cited by 409
“However, it should be noted that IL-1β is not sufficient to cause neurotoxicity or neurodegeneration in the absence of tau [136, 138].”
BackgroundBidirectional Microglia–Neuron Communication in Health and Disease
Szepesi, Z., Manouchehrian, O., Bachiller, S., & Deierborg, T. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00323 · Cited by 459
Rodent models for Alzheimer disease
Götz, J., Bodea, L., & Goedert, M. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0054-8 · Cited by 422
Ghosh, S., Wu, M. D., Shaftel, S. S., Kyrkanides, S., LaFerla, F. M., Olschowka, J. A., & O'Banion, M. K. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4361-12.2013 · Cited by 390
Garwood, C. J., Pooler, A. M., Atherton, J., Hanger, D. P., & Noble, W. (2011) · Cell Death & Disease · doi:10.1038/cddis.2011.50 · Cited by 379
“to the activation of p38 MAPK and tau hyperphosphorylation in vivo.(38) Activation of caspase-3 also occurs downstream of IL-1 receptors,(39) which conceivably results in the”
BackgroundTagge, C. A., Fisher, A. M., Minaeva, O. V., Gaudreau, A., Moncaster, J. A., Zhang, X.-L., Wojnarowicz, M. W., Casey, N. F., Lu, H., Kokiko‐Cochran, O. N., et al. (2017) · Brain · doi:10.1093/brain/awx350 · Cited by 402
Self-citationMattsson-Carlgren, N., Andersson, E., Janelidze, S., Ossenkoppele, R., Insel, P., Strandberg, O., Zetterberg, H., Rosen, H. J., Rabinovici, G., Chai, X., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaz2387 · Cited by 359
“Another possibility is that A is linked to tau indirectly through changes in microglial or astrocytic activity, which in turn induces tau pathology (30).”
González, H., Elgueta, D., Montoya, A., & Pacheco, R. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.07.012 · Cited by 352
Tau and neuroinflammation: what impact for Alzheimer's disease and tauopathies?
Laurent, C., Buée, L., & Blum, D. (2018) · Biomedical Journal · doi:10.1016/j.bj.2018.01.003 · Cited by 348
“Indeed LPS administration in mice deficient for IL-1 receptor fails to induce Tau hyper-phosphorylation [129].”
BackgroundInfluentialMicroglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336
Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
Gomez-Nicola, D., & Perry, V. H. (2015) · The Neuroscientist · doi:10.1177/1073858414530512 · Cited by 340
Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
Henstridge, C. M., Hyman, B. T., & Spires-Jones, T. L. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0113-1 · Cited by 348
Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models
Spangenberg, E. E., & Green, K. N. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.07.003 · Cited by 352
“…between microglia-induced inflammation and neurofilbrillary tangles, researchers found that a deficiency in CX3CR1 in a humanized tau (hTau) mouse model altered microglial activation and increased levels of phosphorylated tau protein, resulting in behavioral impairments (Bhaskar et al., 2010).”
BackgroundTakeshita, Y., & Ransohoff, R. M. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01127.x · Cited by 341
Self-citationMicroglia, seen from the CX3CR1 angle
Wolf, Y., Yona, S., Kim, K.-W., & Jung, S. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00026 · Cited by 316
The role of lipopolysaccharide-induced cell signalling in chronic inflammation
Page, M. J., Kell, D. B., & Pretorius, E. (2022) · Chronic Stress · doi:10.1177/24705470221076390 · Cited by 315
“Indeed, LPS treatment of mice leads to cognitive impairment, which is prevented by TLR4-specific inhibitors.91,92 LPS also activates microglia and disrupts synapses in a mechanism involving microglia-derived IL-1β and loss of synaptophysin in mice.93 Furthermore, LPS stimulation can increase the permeability of the bl…”
BackgroundThe Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 316
“Activated microglia can further induce tau phosphorylation in primary mouse neurons, activating IL1β receptor and p38MAPK stress signaling (272).”
BackgroundMicroglia in Health and Disease
Ransohoff, R. M., & Khoury, J. E. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020560 · Cited by 303
Self-citationMicroglia actions in Alzheimer's disease
Prokop, S., Miller, K. R., & Heppner, F. L. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1182-x · Cited by 291
“In view of the apparent link between brain inflammation and tau pathology [10, 74, 80], it is plausible that Trem2 mutations may serve to promote not only reduced amyloid clearance in early stages of disease, but also tau pathology at later stages.”
BackgroundBemiller, S. M., McCray, T. J., Allan, K., Formica, S. V., Xu, G., Wilson, G., Kokiko-Cochran, O. N., Crish, S. D., Lasagna-Reeves, C. A., Ransohoff, R. M., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0216-6 · Cited by 299
“Previous studies demonstrated that microglia in hTau mice exhibit altered morphology that is accompanied by upregulation of expression of macrophage surface markers in an age and pathology dependent manner [29].”
BackgroundSelf-citationLaurent, C., Dorothée, G., Hunot, S., Martin, E., Monnet, Y., Duchamp, M., Dong, Y., Légeron, F.-P., Leboucher, A., Burnouf, S., et al. (2017) · Brain · doi:10.1093/brain/aww270 · Cited by 303
“In a detrimental circle, microglia activation was suggested to play an important role in the development/spreading of tau pathology and associated memory deficits (Yoshiyama et al., 2007; Gorlovoy et al., 2009; Bhaskar et al., 2010; Nash et al., 2013; Asai et al., 2015).”
BackgroundBachstetter, A. D., Xing, B., de Almeida, L., Dimayuga, E. R., Watterson, D. M., & Van Eldik, L. J. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-79 · Cited by 282
“Blocking p38a MAPK in microglia, a principle source of inflammatory cytokines such as IL-1b, may ameliorate the detrimental sequelae of increases in neuronal tau phosphorylation, synaptic loss, or other cytokine-induced neuronal damage responses [42-45].”
An ADIOL-ERβ-CtBP Transrepression Pathway Negatively Regulates Microglia-Mediated Inflammation
Saijo, K., Collier, J. G., Li, A. C., Katzenellenbogen, J. A., & Glass, C. K. (2011) · Cell · doi:10.1016/j.cell.2011.03.050 · Cited by 295
“To determine whether Indazoles could inhibit inflammation in the brain, we monitored the effect of Indazole-Cl treatment on the expression of pro-inflammatory genes in the substantia nigra following injection of LPS into the peritoneal cavity (Figure 3A), which induces both systemic and CNS inflammation (Bhaskar et al…”
Lopez‐Rodriguez, A. B., Hennessy, E., Murray, C. L., Nazmi, A., Delaney, H. J., Healy, D., Fagan, S. G., Rooney, M., Stewart, E., Lewis, A., et al. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12341 · Cited by 293
Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy
Cherry, J. D., Tripodis, Y., Alvarez, V. E., Huber, B. R., Kiernan, P. T., Daneshvar, D. H., Mez, J., Montenigro, P. H., Solomon, T. M., Alosco, M. L., et al. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0382-8 · Cited by 304
“An activated microglial-mediated increase in ptau is consistent with previous work demonstrating that neuroinflammation increased the activity of GSK3β and p38MAPK, both of which are involved in tau hyperphosphorylation [14] and promote ptau pathology [34].”
ResultStem-cell-derived human microglia transplanted in mouse brain to study human disease
Mancuso, R., Van Den Daele, J., Fattorelli, N., Wolfs, L., Balusu, S., Burton, O., Liston, A., Sierksma, A., Fourne, Y., Poovathingal, S., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0525-x · Cited by 295
The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease
Hopp, S. C., Lin, Y., Oakley, D., Roe, A. D., DeVos, S. L., Hanlon, D., & Hyman, B. T. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1309-z · Cited by 286
Advances in developing novel therapeutic strategies for Alzheimer’s disease
Cao, J., Hou, J., Ping, J., & Cai, D. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0299-8 · Cited by 283
In vivo structure/function and expression analysis of the CX3C chemokine fractalkine
Kim, K.-W., Vallon-Eberhard, A., Zigmond, E., Farache, J., Shezen, E., Shakhar, G., Ludwig, A., Lira, S. A., & Jung, S. (2011) · Blood · doi:10.1182/blood-2011-04-348946 · Cited by 299
Microglia Activation as a Biomarker for Traumatic Brain Injury
Hernandez‐Ontiveros, D. G., Tajiri, N., Acosta, S., Giunta, B. N., Tan, J., & Borlongan, C. V. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00030 · Cited by 292
“In vitro and in vivo models of neurological conditions and brain inflammation also reported how CX3CL1 reduces microglia toxicity and, consequently, neuronal damage (Zujovic et al., 2000; Mizuno et al., 2003; Cardona et al., 2006; Bhaskar et al., 2010; Noda et al., 2011; Pabon et al., 2011).”
BackgroundMicroglia and Memory: Modulation by Early-Life Infection
Williamson, L. L., Sholar, P. W., Mistry, R. S., Smith, S. H., & Bilbo, S. D. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3688-11.2011 · Cited by 274
“Mice deficient in fractalkine receptor, CX3CR1, exhibit enhanced Tau pathology within the HP that is dependent upon microglialderived IL-1 (Bhaskar et al., 2010).”
BackgroundThe Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders
Pawelec, P., Ziemka‐Nałęcz, M., Sypecka, J., & Zalewska, T. (2020) · Cells · doi:10.3390/cells9102277 · Cited by 284
“Conversely, a follow-up study surprisingly revealed that ablation of the fractalkine receptor resulted in enhanced Tau pathology, as demonstrated by increased Tau phosphorylation and aggregation, which correlates with worsened behavioral and cognitive deficits [91,99].”
BackgroundCho, S.-H., Sun, B., Zhou, Y., Kauppinen, T. M., Halabisky, B., Wes, P., Ransohoff, R. M., & Gan, L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.254268 · Cited by 268
Self-citationModels of β-amyloid induced Tau-pathology: The long and “folded” road to understand the mechanism
Stancu, I.-C., Vasconcelos, B., Terwel, D., & Dewachter, I. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-51 · Cited by 256
“And, different reports have demonstrated that Tau-pathology is dramatically aggravated by acute and chronic inflammatory insults that induce micro- or astrogliosis [117-119].”
BackgroundHussain, B., Fang, C., & Chang, J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.688090 · Cited by 255
Priming Microglia for Innate Immune Memory in the Brain
Neher, J. J., & Cunningham, C. M. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.02.001 · Cited by 263
Sierra, A., Beccari, S., Díaz‐Aparicio, I., Encinas, J. M., Comeau, S., & Tremblay, M. (2014) · Neural Plasticity · doi:10.1155/2014/610343 · Cited by 268
“Thismodule forms a unique neuron-microglia signalling unit that controls the extent of microglial inflammation in several neurodegenerative conditions including PD, ALS [127], or AD [128].”
BackgroundCerbai, F., Lana, D., Nosi, D., Petkova-Kirova, P., Zecchi, S., Brothers, H. M., Wenk, G. L., & Giovannini, M. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045250 · Cited by 251
Tau Proteins and Tauopathies in Alzheimer’s Disease
Chong, F. P., Ng, K. Y., Koh, R. Y., & Chye, S. M. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-017-0574-1 · Cited by 260
“The same results were obtained in other in vitro studies (Bhaskar et al. 2010; Maphis et al. 2015).”
ResultEnhanced tau aggregation in the presence of Amyloid β
Bennett, R. E., DeVos, S. L., Dujardin, S., Corjuc, B., Gor, R., Gonzalez, J., Roe, A. D., Frosch, M. P., Pitstick, R., Carlson, G. A., et al. (2017) · The American Journal of Pathology · doi:10.1016/j.ajpath.2017.03.011 · Cited by 245
The Ischemic Environment Drives Microglia and Macrophage Function
Fumagalli, S., Perego, C., Pischiutta, F., Zanier, E. R., & Simoni, M. G. D. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00081 · Cited by 261
“Tau pathology No ↑ MAP phosphorylation, behavioral impairments, ↑ microglial activation, ↑IL-1b (199)”
BackgroundMicroglia in Alzheimer's Disease: Exploring How Genetics and Phenotype Influence Risk
McQuade, A., & Blurton-Jones, M. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.01.045 · Cited by 244
Tau in neurodegenerative disease
Gao, Y.-L., Wang, N., Sun, F.-R., Cao, X.-P., Zhang, W., & Yu, J.-T. (2018) · Annals of Translational Medicine · doi:10.21037/atm.2018.04.23 · Cited by 222
“Transgenic mice deprived of the microglial-specific fractalkine receptor CX3CR1, which exerts an anti-inflammatory impact on microglia, showed aggravating tau pathologies (123).”
BackgroundCellular and pathological functions of tau
Bravo, C. P., Naguib, S. A., & Gan, L. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00753-9 · Cited by 271
Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities
Dorostkar, M. M., Zou, C., Blazquez-Llorca, L., & Herms, J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1449-5 · Cited by 235
“drives tau hyperphosphorylation and aggregation [15, 51],”
Targeting Neuroinflammation to Treat Alzheimer’s Disease
Ardura-Fabregat, A., Boddeke, E., Boza‐Serrano, A., Brioschi, S., Castro‐Gomez, S., Ceyzériat, K., Dansokho, C., Dierkes, T., Gelders, G., Heneka, M. T., et al. (2017) · CNS Drugs · doi:10.1007/s40263-017-0483-3 · Cited by 241
“[136] but worsened tau pathology and lowered cognitive performance [133, 134].”
BackgroundCSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
Mancuso, R., Fryatt, G., Cleal, M., Obst, J., Pipi, E., Monzón-Sandoval, J., Ribe, E., Winchester, L., Webber, C., Nevado, A., et al. (2019) · Brain · doi:10.1093/brain/awz241 · Cited by 235
“, 2004) and inflammatory cytokines, especially IL-1b, can contribute to tau phosphorylation via the activation of MAPK in neurons in hTau mice (Bhaskar et al., 2010; Maphis et al., 2015, 2016).”
BackgroundMicroglia and Alzheimer’s Disease
Merighi, S., Nigro, M., Travagli, A., & Gessi, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112990 · Cited by 236
Corticobasal degeneration: a pathologically distinct 4R tauopathy
Kouri, N., Whitwell, J. L., Josephs, K. A., Rademakers, R., & Dickson, D. W. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2011.43 · Cited by 246
When and How Do Seizures Kill Neurons, and Is Cell Death Relevant to Epileptogenesis?
Dingledine, R. J., Varvel, N. H., & Dudek, F. E. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-94-017-8914-1_9 · Cited by 226
“If interactions between CD200R and CD200 [ 42 , 102 ] or CX3CR1 and CX3CL1 [ 3 , 13 ] are disrupted by signals released during neuronal damage or distress, then microglia are unleashed from this constitutive state of inhibition and a more fl orid microglial response ensues.”
BackgroundTau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220
“However, other insights on the initiation of tau pathology have been proposed, such as the impaired cholesterol metabolism [632], deregulated endocytosis [473,633], or overactivated microglia [634].”
BackgroundAlzheimer’s disease as an inflammatory disease
Bolós, M., Perea, J. R., & Avila, J. (2017) · BioMolecular Concepts · doi:10.1515/bmc-2016-0029 · Cited by 216
“Deficits in tau function affect various neuronal functions, such as the secretion of proteins like fractalkine (CX3CL1) (70, 71).”
BackgroundQin, J., Ma, Z., Chen, X., & Shu, S. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1103416 · Cited by 243
“Specifically, elevated IL-1 caused by CX3CR1 depletion in microglia leads to increased Tau hyperphosphorylation (116).”
BackgroundModulating neurotoxicity through CX3CL1/CX3CR1 signaling
Limatola, C., & Ransohoff, R. M. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00229 · Cited by 210
“…data, together with the observation that microglia-induced MAPT phosphorylation in neurons can be blocked by IL-1Ra and p38 inhibitors further supports the hypothesis that inhibiting production of IL-1β constitutes a central mechanism for CX3CL1 neuroprotective signaling (Bhaskar et al., 2010).”
BackgroundSelf-citationThe immunology of neurodegeneration
Czirr, E., & Wyss‐Coray, T. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58656 · Cited by 218
“While CX3CR1 deficiency also reduced neuronal loss in mice that express a combination of familial AD mutations in APP, presenilin 1, and t (45), it promoted neuronal t pathology and behavioral deficits in mice that express only mutant t (46).”
Inflammation in the early stages of neurodegenerative pathology
Khandelwal, P. J., Herman, A. M., & Moussa, C. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2011.07.002 · Cited by 218
“activated protein kinase (MAPK) (Bhaskar et al., 2010).”
Impact of Cytokines and Chemokines on Alzheimer’s Disease Neuropathological Hallmarks
Domingues, C., da Cruz e Silva, O. A. B., & Henriques, A. G. (2017) · Current Alzheimer Research · doi:10.2174/1567205014666170317113606 · Cited by 203
“Consistently, CX3CR1 receptor deficiency was previously shown to increase TAU phosphorylation [141] and to ameliorate Aβ levels and deposition [142, 143].”
Evans, T. A., Barkauskas, D. S., Myers, J., Hare, E. G., You, J., Ransohoff, R. M., Huang, A. Y.-C., & Silver, J. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.01.013 · Cited by 217
“, 2000), to larger changes in Alzheimer's disease (Bhaskar et al., 2010; Lee et al., 2010), spinal cord injury (Donnelly et al.”
Self-citationLiu, J., Li, H., Gong, T., Chen, W., Mao, S., Kong, Y., Yu, J., & Sun, J. (2020) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c02807 · Cited by 199
CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases
Subbarayan, M. S., Joly‐Amado, A., Bickford, P. C., & Nash, K. R. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107989 · Cited by 204
Amyloid-β and Tau at the Crossroads of Alzheimer’s Disease
Gallardo, G., & Holtzman, D. M. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_16 · Cited by 212
Microglial immune checkpoint mechanisms
Deczkowska, A., Amit, I., & Schwartz, M. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0145-x · Cited by 185
Intersection of pathological tau and microglia at the synapse
Vogels, T., Murgoci, A.-N., & Hromádka, T. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0754-y · Cited by 197
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
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