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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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In the citing paper
“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
“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]
The 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]
The check wasn’t confident either way, so it gives no verdict — never disputed.
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]
Experimental — accuracy not yet measuredIn 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
“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
“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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“Moreover, exciting data demonstrated that the immune challenges could trigger and exacerbate tau and amyloid pathologies (Bhaskar et al., 2010; Krstic et al., 2012), possibly contributing to a pathologicalvicious circle that could favor regulated neuronal death.”
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“Previous studies have suggested a beneficial role of microglia in hTau mice, as deficiency in either of the microglia-specific genes Cx3cr1 or Trem2 exacerbates tau pathology (Bemiller et al., 2017; Bhaskar et al., 2010; Maphis et al., 2015).”
BackgroundChoi, Y., Dunn-Meynell, A. A., Marchese, M. E., Blumberg, B. M., Gaindh, D., Dowling, P. C., & Lü, W. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00766-4 · Cited by 14
Romero‐Molina, C., Navarro, V., Jiménez, S., Muñoz‐Castro, C., Sanchez-Mico, M. V., Gutiérrez, A., Vitórica, J., & Vizuete, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22189734 · Cited by 14
Macroscopic modelling of Alzheimer’s disease: difficulties and challenges
Bertsch, M., Franchi, B., Raj, A., & Tesi, M. C. (2021) · Brain Multiphysics · doi:10.1016/j.brain.2021.100040 · Cited by 14
Inflammation in the CNS: Understanding Various Aspects of the Pathogenesis of Alzheimer's Disease
Doroszkiewicz, J., Mroczko, P., & Kulczyńska‐Przybik, A. (2021) · Current Alzheimer Research · doi:10.2174/1567205018666211202143935 · Cited by 14
“Disturbance in the CX3CL1 signaling axis has been described in several neurodegenerative diseases, including AD, although its specific role has not been fully elucidated to date [103-106].”
Sakakibara, Y., Yamashiro, R., Chikamatsu, S., Hirota, Y., Tsubokawa, Y., Nishijima, R., Takei, K., Sekiya, M., & Iijima, K. (2023) · iScience · doi:10.1016/j.isci.2023.105968 · Cited by 14
Complement receptor 4 mediates the clearance of extracellular tau fibrils by microglia
Yoo, C. J., Choi, Y., Bok, E., Lin, Y., Cheon, M., Lee, Y., & Kim, J. (2024) · FEBS Journal · doi:10.1111/febs.17150 · Cited by 16
Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review
Dunning, E. E., Decourt, B., Zawia, N. H., Shill, H. A., & Sabbagh, M. N. (2024) · Neurology and Therapy · doi:10.1007/s40120-024-00614-9 · Cited by 20
“Current animal studies are investigating strategies to target microglia-specific fractalkine receptors (e.g., CX3CR1), as well as interleukin (IL)-1 b , which may assist in slowing or arresting tau spread [17, 37].”
BackgroundInfluentialYassaghi, Y., Nazerian, Y., Ghasemi, M., Nazerian, A., Sayehmiri, F., Perry, G. L., & Pourbadie, H. G. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18554 · Cited by 15
“58,59 In addition, excessive activation of microglial cells during AD results in reverse outcomes, including synaptic dysfunction, neural destruction, BBB impairment, and increased inflammatory state in the CNS, resulting in behavioural and cognitive dysfunction 39–41 , 60– 62”
BackgroundThe intricate interplay between microglia and adult neurogenesis in Alzheimer’s disease
Früholz, I., & Meyer‐Luehmann, M. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1456253 · Cited by 16
“CX3CR1 deficiency reduced A β load but worsened neuronal and behavioral deficits in a plaque-independent manner in AD mice (Bhaskar et al., 2010; Lee et al., 2010).”
BackgroundFuster-Matanzo, A., Jurado‐Arjona, J., Benvegnù, S., García, E., Martín-Maestro, P., Gómez‐Sintes, R., Hernández, F., & Ávila, J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2408-6 · Cited by 14
“Indeed, contradictory results have been obtained in different mouse models of AD [16, 17].”
ResultKim, B., Vasanthakumar, A., Li, Q. S., Nudelman, K. N. H., Risacher, S. L., Davis, J. W., Idler, K. B., Lee, J., Seo, S. W., Waring, J. F., et al. (2022) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12354 · Cited by 13
Hebron, M. L., Algarzae, N. K., Lonskaya, I., & Moussa, C. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.01.009 · Cited by 14
Kukharsky, M. S., Овчинников, Р. К., & Бачурин, С. О. (2015) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro20151156103-114 · Cited by 15
Modulation of microglia activation and Alzheimer's disease
Suresh, P., Phasuk, S., & Liu, I. Y. (2021) · Tzu Chi Medical Journal · doi:10.4103/tcmj.tcmj_144_20 · Cited by 14
“Another research used the Cxcr1-/-mouse model and demonstrated that after LPS administration, MAPT phosphorylation was elevated in the neurons of knockout mice, which is related to microglia activation, in turn activating toll-like receptor 4 (TLR4) and IL-1 receptors [57].”
MethodGuan, X., Zha, L., Zhu, X., Rao, X., Huang, X., Xiong, Y., Guo, Y., Zhang, M., Zhou, D., Tu, Q., et al. (2025) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2025.5588 · Cited by 14
FGFR3 drives Aβ-induced tau uptake
Kim, D. K., Suh, K. Y., Park, J., Lee, S., Han, J., Chang, S., Kim, Y., & Mook‐Jung, I. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01274-3 · Cited by 14
“The A β -mediated release of proin fl ammatory cytokines from activated microglia enhances tau aggregation 17,18 .”
Therapeutic Targets in Innate Immunity to Tackle Alzheimer’s Disease
Serradas, M. L., Ding, Y., Martorell, P., Kulińska, I., & Castro‐Gomez, S. (2024) · Cells · doi:10.3390/cells13171426 · Cited by 16
“40 [76], and APP/PS1 mouse models [77], the constitutional cx3cr1 deficiency worsens tau pathology in the hTau model [74,78] and accelerates the spread of tau aggregates [79].”
BackgroundChandra, S., & Vassar, R. J. (2024) · Immunological Reviews · doi:10.1111/imr.13412 · Cited by 17
Neuroinflammation and Alzheimer’s disease: lessons learned from 5-lipoxygenase
Joshi, Y. B., & Praticò, D. (2014) · Translational Neuroscience · doi:10.2478/s13380-014-0225-7 · Cited by 12
Yetman, M. J., Fowler, S., & Jankowsky, J. L. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153724 · Cited by 14
Shen, Z., Yang, X., Lan, Y., & Chen, G. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231159 · Cited by 13
Ortiz-Islas, E., Montes, P., Rodríguez-Pérez, C. E., Ruiz-Sánchez, E., Sánchez-Barbosa, T., Pichardo-Rojas, D., Zavala‐Tecuapetla, C., Carvajal, K., & Campos‐Peña, V. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17010128 · Cited by 14
“Recent studies have shown that altered microglial activation promotes tau hyper-phosphorylation and aggregation in neurons [144].”
Anton, P. E., Maphis, N. M., Linsenbardt, D. N., & Coleman, L. G. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-81908-7_10 · Cited by 12
The Strategies for Treating “Alzheimer’s Disease”: Insulin Signaling May Be a Feasible Target
You, G., Yao, J., Liu, Q., & Li, N. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44120421 · Cited by 12
“Chemically or genetically activating microglia significantly accelerated tau pathology and behavioral abnormalities in the human tau mouse model of tauopathy [136,137].”
BackgroundLv, J., Shen, X., Shen, X.-Y., Zhao, S., Xu, R., Yan, Q., Lu, J., Zhu, D., Zhao, Y., Dong, J., et al. (2023) · Phytotherapy Research · doi:10.1002/ptr.7945 · Cited by 12
“:3) mice (Bhaskar et al., 2010), and CX3CR1 knockout worsens AD-related tauopathy and cognitive deficits (Cho et al., 2011).”
Huang, Z. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221042 · Cited by 12
“For example, increased IL-1 (cid:2) signaling has been found to result in tau hyperphosphorylation and aggregation via p38 MAPK in the mouse brain [239].”
Maphis, N. M., Hulse, J. P., Peabody, J., Dadras, S., Whelpley, M. J., Kandath, M., Wilson, C. M., Hobson, S., Thompson, J., Poolsup, S., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70101 · Cited by 10
“28,63,64 We alsoshowed thatblocking IL-1ß signaling via global and genetic knockout of inflammasomes adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain [CARD]) reduced tau pathology and improved spatial memory, which is a consequence of reduced…”
Self-citationHolmes, B. B., Weigel, T. K., Chung, J. M., Kaufman, S. K., Apresa, B. I., Byrnes, J. R., Kumru, K. S., Vaquer‐Alicea, J., Gupta, A., Rose, I. V. L., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00883-4 · Cited by 14
“Emerging experimental data suggest that reactive microglia contribute to the deposition of pathological tau as well as tau-mediated neurodegeneration in AD [18–21], possibly via APOE [22, 23].”
Microglia in Alzheimer’s Disease: A Favorable Cellular Target to Ameliorate Alzheimer’s Pathogenesis
Sumsuzzman, D. M., Uddin, M. S., Kabir, M. T., Hasana, S., Perveen, A., Alanazi, I. S., Albadrani, G. M., Abdel‐Daim, M. M., & Ashraf, G. M. (2022) · Mediators of Inflammation · doi:10.1155/2022/6052932 · Cited by 12
“Interestingly, an in vivo humanized mouse model of tauopathy (hTau) showed that either chemical compound or genetically induced microglial triggering markedly manifested tau pathology and behavioral malformation [154].”
BackgroundMaksour, S., & Ooi, L. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15885 · Cited by 12
“…activation drives tau pathology through increased spreading via exosome secretion (Asai et al., 2015), increasing hyperphosphorylation in neurons (Bhaskar et al., 2010; Maphis et al., 2015) and NLRP3 activation increasing tau aggregation and seeding (Ising et al., 2019; Stancu et al., 2019).”
BackgroundDunn-Meynell, A. A., Dowling, P. C., Marchese, M. E., Rodríguez, E., Blumberg, B. M., Choi, Y., Gaindh, D., & Lü, W. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00252 · Cited by 10
Marcondes, M. C. G., Ojakian, R., Bortell, N., Flynn, C. T., Conti, B., & Fox, H. S. (2014) · Mediators of Inflammation · doi:10.1155/2014/358218 · Cited by 12
Katsumoto, A., Kokiko‐Cochran, O. N., Bemiller, S. M., Xu, G., Ransohoff, R. M., & Lamb, B. T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.978423 · Cited by 11
“Frontiers in Immunology 03 staining was performed as described (30).”
MethodSelf-citationChronic inflammation: a potential target in tauopathies
Ising, C., & Heneka, M. T. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00116-3 · Cited by 10
Xu, B., Tang, C., Han, R., Zhu, C., Yang, Y., Li, H. J., Wu, N., & He, D. (2025) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823251326044 · Cited by 10
“96,97 In summary, neurons produce CX3CL1, which regulates MG activation and function through interaction with its receptor, CX3CR1, on MG.”
Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau
Iyer, A. K., Vermunt, L., Mirfakhar, F. S., Minaya, M., Acquarone, M., Koppisetti, R. K., Renganathan, A., You, S., Danhash, E., Schache, K. J., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03073-2 · Cited by 14
“Additionally, microglia-derived secretory factors and their proin fl ammatory state may initiate tau aggregation in neurons in tauopathy mouse models [88, 89, 91 – 93].”
Neuroinflammation als Motor der Alzheimer-Erkrankung
Castro‐Gomez, S., Binder, J., & Heneka, M. T. (2019) · Der Nervenarzt · doi:10.1007/s00115-019-0778-3 · Cited by 11
Roles of Microglia in AD Pathology
Gao, R., Wu, H., Li, Q., & Zhao, J. (2023) · Current Alzheimer Research · doi:10.2174/1567205020666230203112351 · Cited by 10
Wang, X., Wang, H., Yi, P., Baker, C. K., Casey, G., Xie, X., Luo, H., Cai, J., Fan, X., Soong, L., et al. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110512 · Cited by 10
C-Reactive Protein Induces Tau Hyperphosphorylation via GSK3β Signaling Pathway in SH-SY5Y Cells
Guo, H., Wang, H., Wang, C., Cheng, Y., Zou, Z., Li, Y., Wu, J., & Xu, J. (2015) · Journal of Molecular Neuroscience · doi:10.1007/s12031-015-0572-z · Cited by 11
“Aβ- and inflammation-induced hyperphosphorylation of tau have been well documented by various researchers (Li et al. 2003; Quintanilla et al. 2004; Kitazawa et al. 2005; Hernandez et al. 2009; Bhaskar et al. 2010).”
BackgroundHeadmasters: Microglial regulation of learning and memory in health and disease
Weinhard, L., d’Errico, P., & Tay, T. L. (2018) · AIMS molecular science · doi:10.3934/molsci.2018.1.63 · Cited by 11
“Contrary to the potential beneficial effect on Aβ plaque deposition, Cx3cr1 knockout in hAPP or hTau mouse models increased microglia activation, enhanced MAPT phosphorylation and aggregation, as well as exacerbated calbindin depletion in the hippocampus and memory impairment [187–189] (Figure 2).”
Carlomagno, Y., Chung, D. C., Yue, M., Kurti, A., Avendano, N. M., Castanedes‐Casey, M., Hinkle, K. M., Jansen‐West, K. R., Daughrity, L. M., Tong, J., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0661-2 · Cited by 10
Targeting tau in Alzheimer’s Disease: rationale, approach and challenges
Aslanyan, A., Foiani, M. S., Giovannucci, T. A., McDade, E., Duff, K., Mummery, C. J., Schöll, M., Wildsmith, K. R., & Paterson, R. W. (2026) · Molecular Neurodegeneration · doi:10.1186/s13024-026-00925-5 · Cited by 10
“CX3CR1 which is expressed in microglia and is responsible for regulating the efficiency of extracellular tau internalization and clearance, can cause excessive tau spread with genetic disruption [106, 107].”
Blood–brain barrier and neurological diseases
Takeshita, Y., & Ransohoff, R. M. (2015) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12229 · Cited by 12
Self-citationXia, Y., Chen, C., Chen, J., Hu, C., Yang, W., Wang, L., Liu, L., Gao, L.-P., Wu, Y.-Z., Chen, D.-D., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02989-y · Cited by 7
Voltage-Gated Na+ Channels in Alzheimer’s Disease: Physiological Roles and Therapeutic Potential
Baumgartner, T. J., Haghighijoo, Z., Goode, N. A., Dvorak, N. M., Arman, P., & Laezza, F. (2023) · Life · doi:10.3390/life13081655 · Cited by 10
pS396/pS404 (PHF1) tau vaccine outperforms pS199/pS202 (AT8) in rTg4510 tauopathy model
Hulse, J. P., Maphis, N. M., Peabody, J., Bondu, V., Chackerian, B., & Bhaskar, K. (2025) · npj Vaccines · doi:10.1038/s41541-025-01147-4 · Cited by 9
“The Sarkosyl-insoluble fraction of tau was isolated from hippocampal samples as described previously 69,84 .”
Self-citationMicrobiota and Alzheimer’s disease: mechanistic insights from a multi-organ perspective
Liao, J., Mou, H., Luo, S., Shen, L., & Jiao, B. (2026) · Translational Neurodegeneration · doi:10.1186/s40035-026-00541-9 · Cited by 11
The Role of Aβ and Tau Oligomers in the Pathogenesis of Alzheimer’s Disease
Bhaskar, K., & Lamb, B. T. (2011) · Springer eBooks · doi:10.1007/978-94-007-2774-8_5 · Cited by 8
Self-citationStructural fingerprinting of pleiotropic flavonoids for multifaceted Alzheimer's disease
Punmiya, A., & Prabhu, A. (2023) · Neurochemistry International · doi:10.1016/j.neuint.2023.105486 · Cited by 9
Stojić-Vukanić, Z., Pilipović, I., Djikić, J., Vujnović, I., Nacka-Aleksić, M., Bufan, B., Arsenović-Ranin, N., Kosec, D. J., & Leposavić, G. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.11.002 · Cited by 9
Astrocytes and Inflammatory Processes in Alzheimer’s Disease
Vallés, S. L., Burguet, F., Iradi, A., Aldasoro, M., Vila, J. M., Aldasoro, C., & Jorda, A. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.88701 · Cited by 9
Sex as a determinant of age-related changes in rat spinal cord inflammation-oxidation state
Nacka-Aleksić, M., Stojanović, M., Simic, L., Bufan, B., Kotur‐Stevuljević, J., Stojić-Vukanić, Z., Dimitrijević, M., Ražić, S., & Leposavić, G. (2017) · Biogerontology · doi:10.1007/s10522-017-9726-4 · Cited by 9
“It should be pointed out that inhibited production of IL-1b constitutes a central mechanism for CX3CL1 neuroprotective signaling (Bhaskar et al. 2010), and that IL-1b action has been consistently associated with neurodegeneration in vivo (Zujovic et al.”
Goode‐Romero, G., & Domı́nguez, L. (2022) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2022.108278 · Cited by 7
Malamon, J. S., & Kriete, A. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00228 · Cited by 9
“MAPT pathologies provide a mechanistic link between the immune system and neurodegeneration involving microglia activation (Bhaskar et al., 2010).”
BackgroundDNA-PK and P38 MAPK: A Kinase Collusion in Alzheimer’s Disease?
Kanungo, J. (2017) · Brain Disorders & Therapy · doi:10.4172/2168-975x.1000232 · Cited by 7
“Other contributors to AD pathogenesis include apolipoprotein E genotype [7]; neurofilament and Tau hyperphosphorylation [8-11], and Aβ generation [12].”
BackgroundMedina, C. S., Uselman, T. W., Barto, D. R., Chaves, F. L., Jacobs, R. E., & Bearer, E. L. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00501 · Cited by 7
“Briefly, 10 mg of brain was first homogenized in ice-cold Tissue-Protein Extraction Reagent (T-PER, 78510; Pierce, now Thermo Fisher Scientific, Waltham, MA) with protease (P8340; Sigma-Aldrich) and phosphatase (P5726; Sigma-Aldrich) inhibitor cocktails with a Dounce homogenizer for 1 minute, and then sonicated in a B…”
MethodSystemic Infections May Cause Cognitive Deterioration and Neurodegeneration*
Chiu, M. (2014) · Critical Care Medicine · doi:10.1097/ccm.0000000000000205 · Cited by 7
“Furthermore, tau pathology within the hippocampus is dependent on microglia-derived IL-1β (12).”
BackgroundCX3CR1 modulates migration of resident microglia towards brain injuryPreprint
Wagner, J., Hoyer, C., Antony, H., Lundgrén, K., Soliymani, R., Crux, S., Justus, L. C., Keppler, K., Steffen, J., Kurts, C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.23.614458 · Cited by 7
“Thus, microglial Cx3cr1 - deficiency can be either detrimental or beneficial depending on the lesion context 16–18 .”
BackgroundTurner, A. K., Shaw, B. C., Simpson, J. F., & Estus, S. (2022) · Genes · doi:10.3390/genes13091607 · Cited by 7
Iemmolo, M., Bivona, G., Piccoli, T., Nicosia, A., Schiera, G., Liegro, C. M. D., Pietra, F. D., & Ghersi, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052510 · Cited by 6
“It has been suggested that at the onset of AD, the intra-neuronal accumulation of β -amyloid causes a slight decrease in CX3CL1/CX3CR1 signaling, resulting in increased A β phagocytosis and the hyperphosphorylation of tau [4].”
BackgroundTime-Dependent Long-Term Effect of Memantine following Repetitive Mild Traumatic Brain Injury
Boucher, M. L., Conley, G. M., Morriss, N. J., Ospina-Mora, S., Qiu, J., Mannix, R., & Meehan, W. P., III (2024) · Journal of Neurotrauma · doi:10.1089/neu.2023.0423 · Cited by 6
Determinants of regeneration in the injured nervous system
Selzer, M. A., Clarke, S., Cohen, L. G., Kwakkel, G., & Miller, R. H. (2014) · Cambridge University Press eBooks · doi:10.1017/cbo9780511995583.025 · Cited by 6
Neuroinflammation in Traumatic Brain Injury
Kuo, G. Y., Tarzi, F. P., Louie, S. G., & Poblete, R. A. (2022) · IntechOpen eBooks · doi:10.5772/intechopen.105178 · Cited by 7
Takuwa, H., Orihara, A., Takado, Y., Urushihata, T., Shimojo, M., Ishikawa, A., Takahashi, M., Barron, A. M., Ono, M., Maeda, J., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.04.368977 · Cited by 6
Kofman, S., Sun, X., Ogbolu, V. C., Ibric, L., & Qiang, L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.30.547293 · Cited by 6
Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States
Kuhn, M. K., & Proctor, E. A. (2024) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26723 · Cited by 5
“However, knockdown of CX3CR1 in mice expressing human tau resulted in increased tau hyperphosphorylation, tau aggregation, and microglial activation [107].”
Li, W., Han, Y., Wang, P., & Qiao, S. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70803 · Cited by 6
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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