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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]
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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]
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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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Jung, S., Aliberti, J., Graemmel, P., Sunshine, M. J., Kreutzberg, G. W., Sher, A., & Littman, D. R. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.11.4106-4114.2000 · Cited by 2,632 · cited 2×
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“Interestingly, our previous studies demonstrated that administration of LPS to Cx3cr1 / mice induces neurodegeneration that is also dependent upon IL-1 signaling (Cardona et al., 2006), suggesting that IL-1 may represent as an important signaling molecule between microglia and neurons.”
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The role of microglia in adult hippocampal neurogenesis
Gemma, C., & Bachstetter, A. D. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00229 · Cited by 202
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CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents
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“, 2010) but also with the enhanced microtubule-associated protein tau phosphorylation (Bhaskar et al., 2010), suggesting opposite effects at different phases of the disease.”
BackgroundInfluentialCerebral dysfunctions caused by sepsis during ageing
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Targeting microglia for the treatment of Alzheimer’s Disease
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BackgroundResultInfluentialThe link between chronic pain and Alzheimer’s disease
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“On the other hand, a significant activation of p38 MAPK and increased tau phosphorylation and aggregation in neurons is observed after crossing CX3CR1 knockout mice with tau transgenic mice [154].”
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d’Errico, P., & Meyer‐Luehmann, M. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00265 · Cited by 191
Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice
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“Studies of Cx3cr1 gfp/gfp knock-in mice, in which the Cx3cr1 gene has been replaced by Gfp, have revealed that CX3CR1-deficient microglia show excessive cellular activation and overproduction of inflammatory mediators, generally increasing susceptibility to CNS inflammatory diseases 17,23 .”
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“Specifically, proinflammatory cytokines TNFα, IL1β, and IL6 and inflammasome activation have been shown to directly promote tau phosphorylation in neurons (42, 46, 47).”
BackgroundHuman neural stem cells alleviate Alzheimer-like pathology in a mouse model
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“Alternatively, decreased expression of IL-1β in hNSC-transplanted transgenic mouse brains may reverse tau phosphorylation, as it was reported that the release of IL-1β from microglia stimulates tau phosphorylation [67].”
BackgroundThe role of inflammation in sporadic and familial Parkinson’s disease
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BackgroundInfluentialTau Oligomers and Fibrils Induce Activation of Microglial Cells
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“In the CNS, fractalkine signaling mediates interactions between neurons and microglia (Cardona et al., 2006; Bhaskar et al., 2010; Paolicelli et al., 2011).”
BackgroundFractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis
Lastres-Becker, I., Innamorato, N. G., Jaworski, T., Rábano, A., Kügler, S., Van Leuven, F., & Cuadrado, A. (2014) · Brain · doi:10.1093/brain/awt323 · Cited by 160
“Therefore, although some of these markers are NRF2-dependent, modulation of phagocytosis and cytokine release by CX3CL1 may require additional inflammatory stimuli as suggested by Bhaskar et al. (2010).”
InfluentialSchnöder, L., Hao, W., Qin, Y., Liu, S., Tomic, I., Liu, X., Fassbender, K. C., & Liu, Y. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.695916 · Cited by 146
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“Bhaskar and colleagues [54] showed that transgenic mice lacking CX3CR1 and expressing human tau isoforms had markedly increased numbers of tangle-bearing neurons.”
BackgroundMicroglial polarization: novel therapeutic mechanism against Alzheimer’s disease
Yao, K., & Zu, H. (2019) · Inflammopharmacology · doi:10.1007/s10787-019-00613-5 · Cited by 150
Signaling pathways in macrophages: molecular mechanisms and therapeutic targets
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Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology
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“Furthermore, hyperphosphorylation of tau in this model was mediated by upregulation of p38α the MAPK pathway, but not GSK3β or CDK5 pathways [22].”
InfluentialSelf-citationChauhan, S., Ahmed, Z., Bradfute, S. B., Arko‐Mensah, J., Mandell, M. A., Choi, S. W., Kimura, T., Blanchet, F. P., Waller, A., Mudd, M. H., et al. (2015) · Nature Communications · doi:10.1038/ncomms9620 · Cited by 139
“Second, inflammatory signals were provided to accentuate further tau phosphorylation (occurring on S202 and S396/S404), which in turn promotes further aggregation 57 .”
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Formation and Propagation of Tau Oligomeric Seeds
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Functional and structural damage of neurons by innate immune mechanisms during neurodegeneration
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Microglia in Alzheimer's Disease: Risk Factors and Inflammation
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“Moreover, loss of microglial CX3CR1 has opposing effects Aβ and tau pathologies (23, 24).”
BackgroundNeuroinflammation and fractalkine signaling in Alzheimer’s disease
Finneran, D. J., & Nash, K. R. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1412-9 · Cited by 132
“Furthermore, they observed in CX3CR1-deficient mice, systemic administration of LPS was sufficient to cause phosphorylation of endogenous tau at the paired helical filament-associated sites AT8 and AT180 [11].”
BackgroundInfluentialNG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis
Zhang, S.-Z., Wang, Q., Yang, Q., Gu, H., Yin, Y., Li, Y., Hou, J., Chen, R., Sun, Q., Sun, Y., et al. (2019) · BMC Medicine · doi:10.1186/s12916-019-1439-x · Cited by 141
“Previous studies have reported seemingly conflicting results regarding the effect of CX3CR1 on different brain disease pathologies [12, 52, 53].”
ResultInflammatory aspects of Alzheimer’s disease
Lucena, P. B., & Heneka, M. T. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02790-2 · Cited by 152
“The activation of microglia and the subsequent propagation of tau pathology could potentially be driven by the joint action of several agents like pro-inflammatory cytokines (IL-1β) [117], transcription factors (NF-κB) [248], and signaling pathways (CX3CL1/CX3CR1) [19].”
Morganti, J. M., Nash, K. R., Grimmig, B. A., Ranjit, S., Small, B. J., Bickford, P. C., & Gemma, C. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0539-12.2012 · Cited by 141
Microglial Malfunction: The Third Rail in the Development of Alzheimer's Disease
Mhatre, S. D., Tsai, C. A., Rubin, A. J., James, M. L., & Andreasson, K. I. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.08.006 · Cited by 134
“Ablation of CX3CR1 aggravates tau pathology in mouse models of tauopathy and amyloid accumulation [88,103], and increases proinflammatory cytokine signaling [103] and LPS-induced tau hyperphosphorylation [88].”
InfluentialThe endotoxin hypothesis of Alzheimer’s disease
Brown, G. C., & Heneka, M. T. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00722-y · Cited by 148
“A role of microglia is also suggested by the finding that knockout of the microglia-specific fractalkine receptor CX3CR1 increases LPS-induced tau phosphorylation, aggregation, neuroinflammation and cognitive impairment in an hTau mouse model of tauopathy (Bhaskar et al. 2010).”
BackgroundInsulin dysfunction and Tau pathology
Khoury, N. B. E., Gratuze, M., Papon, M.-A., Bretteville, A., & Planel, E. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00022 · Cited by 133
“Therefore, Bhaskar et al. have suggested that the CX3CL1/CX3CR1 pathway could modulate Tau pathology, and that this effect might be dependent upon microglialderived IL-1-p38 MAPK signaling pathway (Bhaskar et al., 2010).”
BackgroundHu, X., Liou, A. K. F., Leak, R. K., Xu, M., An, C., Suenaga, J., Shi, Y., Gao, Y., Zheng, P., & Chen, J. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2014.06.002 · Cited by 139
Microglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
Condello, C., Yuan, P., & Grutzendler, J. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.007 · Cited by 131
“However, systemic suppression of CX3CR1 signaling may disrupt bacterial clearance by the peripheral immune system (129), while CX3CR1 deficiency may exacerbate tau hyperphosphorylation (130,131).”
Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention
Zhang, G., Wang, Z., Hu, H., Zhao, M., & Sun, L. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.749587 · Cited by 137
The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
Kokiko-Cochran, O. N., & Godbout, J. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00672 · Cited by 128
Self-citationTrem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00562-8 · Cited by 127
Piirainen, S., Youssef, A. M., Song, C., Kalueff, A. V., Landreth, G. E., Malm, T., & Tian, L. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.046 · Cited by 130
Crucial role of protein oligomerization in the pathogenesis of Alzheimer's and Parkinson's diseases
Choi, M. L., & Gandhi, S. (2018) · FEBS Journal · doi:10.1111/febs.14587 · Cited by 131
Wang, H., Yang, F., Zhang, S., Xin, R., & Sun, Y. (2021) · npj Parkinson s Disease · doi:10.1038/s41531-021-00213-7 · Cited by 135
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Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review
Edler, M. K., Mhatre-Winters, I., & Richardson, J. R. (2021) · Cells · doi:10.3390/cells10051138 · Cited by 126
Targeting innate immunity for neurodegenerative disorders of the central nervous system
Andreasson, K. I., Bachstetter, A. D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D. C., Low, D., Lynch, M. A., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13667 · Cited by 126
Self-citationOpposing Effects of Membrane-Anchored CX3CL1 on Amyloid and Tau Pathologies via the p38 MAPK Pathway
Lee, S., Xu, G., Jay, T. R., Bhatta, S., Kim, K.-W., Jung, S., Landreth, G. E., Ransohoff, R. M., & Lamb, B. T. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.0853-14.2014 · Cited by 123
“By contrast, inflammatory cytokine-mediated p38 MAPK activation in neurons has been consistently linked to exacerbation of MAPT pathology (Li et al., 2003; Bhaskar et al., 2010).”
BackgroundSelf-citationNeuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
Bevan-Jones, W. R., Cope, T. E., Jones, P. S., Kaalund, S. S., Passamonti, L., Allinson, K., Green, O., Hong, Y. T., Fryer, T. D., Arnold, R., et al. (2020) · Brain · doi:10.1093/brain/awaa033 · Cited by 124
“, 2007) and pro-inflammatory molecules increase tau hyperphosphorylation and aggregation (Bhaskar et al., 2010).”
BackgroundThinking laterally about neurodegenerative proteinopathies
Golde, T. E., Borchelt, D., Giasson, B. I., & Lewis, J. M. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66029 · Cited by 126
Microglia in Alzheimer’s Disease in the Context of Tau Pathology
Perea, J. R., Bolós, M., & Ávila, J. (2020) · Biomolecules · doi:10.3390/biom10101439 · Cited by 134
“Conversely, the absence of this receptor in a mouse model of tauopathy increases tau hyperphosphorylation and aggregation and amplifies microglial activation, thereby causing IL-1β secretion [124,240].”
BackgroundAguzzi, A., & Zhu, C. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90605 · Cited by 122
Modulation of inflammation in transgenic models of Alzheimer’s disease
Birch, A. M., Katsouri, L., & Sastre, M. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-25 · Cited by 121
“htau(7) CxCR3-GFP ki ↑p-tau, ↑Gallyas-positive dystrophic neurites, ↓Iba1, ↑microglial activation (CD68 and CD45) [66]”
Alzheimer’s Disease, Inflammation, and the Role of Antioxidants
Sinyor, B., Mineo, J., & Ochner, C. (2020) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-200171 · Cited by 120
“AD transgenic mice with a CX3CR1 deletion led to increased tau phosphorylation, accumulation, microglial activation, and an increased deficit in hippocampal learning, exacerbating AD [9, 13].”
BackgroundPuntambekar, S. S., Moutinho, M., Lin, P. B.-C., Jadhav, V., Tumbleson-Brink, D., Balaji, A., Benito, M. A., Xu, G., Oblak, A., Lasagna-Reeves, C. A., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00545-9 · Cited by 113
“Taken together with published studies showing that increased pTau pathology in hTau;Cx3cr1−/− mice is driven by microglial IL-1β [23, 24], our data suggests that Cx3cr1 deficiency may drive pTau accumulation in 5xFAD mice via microglial TREM2-IL1β signaling.”
BackgroundInfluentialSelf-citationGuedes, J. R., Lao, T., Cardoso, A. L., & El Khoury, J. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00549 · Cited by 115
“Moreover, hTau mice (which exhibit p-τ ) lacking CX3CR1 exhibited enhanced tau phosphorylation and aggregation associated with microglial activation, as well as behavioral impairments (35, 66).”
BackgroundMicroglia-Astrocyte Communication in Alzheimer’s Disease
Wu, Y., & Eisel, U. L. M. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230199 · Cited by 125
“Alterationsinmicroglialactivationhavebeenconsis-tently noted in tauopathy animals [104].”
Assessing the contribution of inflammation in models of Alzheimer's disease
Johnston, H. R., Boutin, H., & Allan, S. M. (2011) · Biochemical Society Transactions · doi:10.1042/bst0390886 · Cited by 114
Astrocytes and neuroinflammation in Alzheimer's disease
Phillips, E. C., Croft, C. L., Crane, K., O’Neill, M. J., Hutton, M. L., Hanger, D. P., Garwood, C. J., & Noble, W. J. (2014) · Biochemical Society Transactions · doi:10.1042/bst20140155 · Cited by 115
The role of the immune system in Alzheimer’s disease
Wu, K., Zhang, Y.-R., Huang, Y., Dong, Q., Tan, L., & Yu, J. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101409 · Cited by 119
Patterns of microglial cell activation in frontotemporal lobar degeneration
Lant, S. B., Robinson, A. C., Thompson, J. C., Rollinson, S., Pickering‐Brown, S., Snowden, J. S., Davidson, Y. S., Gerhard, A., & Mann, D. M. A. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12092 · Cited by 102
“studies have also implied this [37,38].”
Agosta, F., Dalla Libera, D., Spinelli, E. G., Finardi, A., Canu, E., Bergami, A., Bocchio Chiavetto, L., Baronio, M., Comi, G., Martino, G., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24235 · Cited by 113
“It would also fit with the hypothesis that activation of microglia, reflected by increased MMV release in the CSF, causes Tau hyperphosphorylation and aggregation within neurons, and consequent neurodegeneration.(49) Furthermore, it has also been shown that CSF extracellular vesicles from AD patients contain p-Tau,(50…”
BackgroundAmbegaokar, S. S., & Jackson, G. R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr432 · Cited by 113
“Phospho-p38 is increased relative to phospho-ERK in AD, CBD and PSP (155), in AD mouse models (151) and tauopathy mouse models (156).”
BackgroundPeixoto, C. A., Nunes, A. K. S., & García‐Osta, A. (2015) · Mediators of Inflammation · doi:10.1155/2015/940207 · Cited by 113
“Microglial-derived interleukin 1 (IL-1) is also associated with phosphorylation and the aggregation of microtubule-associated protein tau (MAPT), a neuropathological feature of tau diseases [61].”
BackgroundFractalkine overexpression suppresses tau pathology in a mouse model of tauopathy
Nash, K. R., Lee, D. C., Hunt, J. B., Morganti, J. M., Selenica, M.-L., Moran, P., Reid, P., Brownlow, M., Guang-Yu Yang, C., Savalia, M., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.011 · Cited by 108
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript CX3CR1−/− mice with a human tau line resulted in an increase in tau pathology (Bhaskar et al., 2010).”
BackgroundTime-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury
Febinger, H. Y., Thomasy, H. E., Pavlova, M. N., Ringgold, K. M., Barf, P. R., George, A. M., Grillo, J. N., Bachstetter, A. D., Garcia, J. A., Cardona, A. E., et al. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0386-5 · Cited by 110
“For instance, in a model of Alzheimer ’ s disease (AD), CX3CR1-deficient microglia from mice overexpressing hTau have increased hyperphosphorylated tau and more toxicity, as has been observed in other animal ’ s disease models [5, 17 – 20].”
Self-citationfor the REVERSE-SD Study Investigators, Prins, N. D., Harrison, J., Chu, H., Blackburn, K., Alam, J. J., & Scheltens, P. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00843-2 · Cited by 110
“Tau phosphorylation and tau pathology have been identified in preclinical studies as downstream consequences of abnormally high p38α kinase activity [10, 16, 20].”
BackgroundKapoor, M., & Chinnathambi, S. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02751-8 · Cited by 114
“The same study employed human MAPT transgenic mice lacking CX3CR1 and revealed that CX3CR1 deletion augments hyperphosphorylation and aggregation of MAPT along with behavioural decline [58].”
BackgroundLiu, L. A., Kim, S., Buckley, M. T., Reyes, J. M., Kang, J., Tian, L., Wang, M., Lieu, A. C., Mao, M., Rodríguez-Mateo, C., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.03.016 · Cited by 115
Fractalkine Over Expression Suppresses α-Synuclein-mediated Neurodegeneration
Nash, K. R., Moran, P., Finneran, D. J., Hudson, C., Robinson, J., Morgan, D., & Bickford, P. C. (2014) · Molecular Therapy · doi:10.1038/mt.2014.175 · Cited by 107
“Interestingly, a cross between CX3CR1 mice with a human tau line (hTau) resulted in an increase in tau pathology [29].”
BackgroundTelomere shortening reduces Alzheimer’s disease amyloid pathology in mice
Rolyan, H., Scheffold, A., Heinrich, A., Begus-Nahrmann, Y., Langkopf, B. H., Hölter, S. M., Vogt-Weisenhorn, D. M., Liss, B., Wurst, W., Lie, D. C., et al. (2011) · Brain · doi:10.1093/brain/awr133 · Cited by 106
“In another mouse model it was observed that CX3CR1-deficiency and resulting higher activity of microglia correlated with increased Tau pathology, suggesting that microglia activation can also have adverse effects on Alzheimer’s disease-associated pathology (Bhaskar et al., 2010).”
BackgroundRole of Microglial Cells in Alzheimer’s Disease Tau Propagation
Španić, E., Horvat, L. L., Hof, P. R., & Šimić, G. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00271 · Cited by 112
“Elevated tau phosphorylation and aggregation were noticed in the absence of TREM2 or fractalkine receptor (Bhaskar et al., 2010; Maphis et al., 2015; Bemiller et al., 2017).”
BackgroundCx3cr1- deficient microglia exhibit a premature aging transcriptome
Gyoneva, S., Hosur, R., Gosselin, D., Zhang, B., Ouyang, Z., Cotleur, A. C., Peterson, M., Allaire, N., Challa, R., Cullen, P., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900453 · Cited by 103
“…in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson ’ s disease and in tauopathies such as frontotemporal dementia, but promotes amyloid clearance in models of amyloid β deposition (Cardona et al, 2006; Bhaskar et al, 2010; Lee et al, 2010; Liu et al, 2010).”
Self-citationWijeyekoon, R., Kronenberg‐Versteeg, D., Scott, K. M., Hayat, S., Kuan, W., Evans, J., Breen, D. P., Cummins, G. A., Jones, J., Clatworthy, M. R., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.01.018 · Cited by 105
“, 2005), with LPS stimulation leading to increased tau production (Bhaskar et al., 2010)(Gardner et al.”
BackgroundJoly‐Amado, A., Hunter, J., Quadri, Z., Zamudio, F., Rocha-Rangel, P., Chan, D., Kesarwani, A., Nash, K. R., Lee, D. C., Morgan, D., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00997 · Cited by 105
“Similarly, mice deficient for fractalkine where characterized by increased CD45 and CD68 levels as well as worsening in tau pathology (50).”
BackgroundMicroglia dynamics in aging-related neurobehavioral and neuroinflammatory diseases
Javanmehr, N., Saleki, K., Alijanizadeh, P., & Rezaei, N. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02637-1 · Cited by 106
“In line with a pathological function for cytokine secretion, the progression of tau neuropathology in Cx3cr1-knockout rodents was inhibited with IL-1 suppression [167], and detrimental influences of apoE4 in the context of tau neuropathology were linked to augmented TNF-α synthesis via microglia in vitro.”
Chidambaram, H., Das, R. R., & Chinnathambi, S. (2020) · Cell & Bioscience · doi:10.1186/s13578-020-00474-4 · Cited by 97
Role of Chemokines in the Development and Progression of Alzheimer’s Disease
Wojcieszak, J., Kuczyńska, K., & Zawilska, J. B. (2022) · Journal of Molecular Neuroscience · doi:10.1007/s12031-022-02047-1 · Cited by 97
“Of note, these animals exhibited pronounced behavioral impairments (Bhaskar et al. 2010).”
BackgroundFrom development to dysfunction: Microglia and the complement cascade in CNS homeostasis
Zabel, M. K., & Kirsch, W. M. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2013.02.001 · Cited by 100
“Bhaskar et al. (2010), Cho et al.”
ABCA1 influences neuroinflammation and neuronal death
Karasinska, J. M., de Haan, W., Franciosi, S., Ruddle, P., Fan, J., Kruit, J. K., Stukas, S., Lütjohann, D., Gutmann, D. H., Wellington, C. L., et al. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.01.018 · Cited by 104
Diverse activation of microglia by chemokine (C-C motif) ligand 2 overexpression in brain
Selenica, M. B., Alvarez, J. A., Nash, K. R., Lee, D. C., Cao, C., Lin, X., Reid, P., Mouton, P. R., Morgan, D., & Gordon, M. N. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-86 · Cited by 99
“Recent evidence derived using genetically modified animal models of amyloid deposition suggests that infiltrating macrophages reduce amyloid deposits [15-18,86,87].”
BackgroundNeuroinflammation in Multiple System Atrophy: Response to and Cause of α-Synuclein Aggregation
Vieira, B. D. M., Radford, R. A., Chung, R. S., Guillemin, G. J., & Pountney, D. L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00437 · Cited by 93
Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23
Leem, Y., Lee, Y.-I., Son, H.-J., & Lee, S. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.02.046 · Cited by 93
Jiang, S., Maphis, N. M., Binder, J., Chisholm, D., Weston, L., Duran, W., Peterson, C., Zimmerman, A., Mandell, M. A., Jett, S. D., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109720 · Cited by 92
“Cell lysates and supernatant were resolved via SDS-PAGE and immunoblotted as previously described (Bhaskar et al., 2010).”
InfluentialSelf-citationChen, Z., Ross, J., & Hambardzumyan, D. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1902366116 · Cited by 102
Calabrese, G., Molzahn, C. M., & Mayor, T. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102062 · Cited by 92
“Recent work also suggests that microglial cells activated by Aβ may play an important role in promoting phosphorylation of tau, notably via the activation of the p38 mitogen-activated protein (MAP) kinase (131).”
BackgroundVojtechova, I., Machacek, T., Kristofikova, Z., Stuchlik, A., & Petrasek, T. (2022) · PLOS Pathogens · doi:10.1371/journal.ppat.1010929 · Cited by 92
“This might initiate hyperphosphorylation of tau protein that promotes AD pathology [33,34].”
BackgroundLoss of tau rescues inflammation-mediated neurodegeneration
Maphis, N., Xu, G., Kokiko-Cochran, O. N., Cardona, A. E., Ransohoff, R. M., Lamb, B. T., & Bhaskar, K. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00196 · Cited by 91
Self-citationAcute microglia ablation induces neurodegeneration in the somatosensory system
Rubino, S. J., Mayo, L., Wimmer, I., Siedler, V., Brunner, F., Hametner, S., Madi, A., Lanser, A., Moreira, T., Donnelly, D., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05929-4 · Cited by 91
Partial reduction of microglia does not affect tau pathology in aged mice
Bennett, R. E., Bryant, A., Hu, M., Robbins, A. B., Hopp, S. C., & Hyman, B. T. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1348-5 · Cited by 91
“enhanced tau phosphorylation via increased activity of p38 MAPK [5, 30].”
BackgroundInfluentialTau at the interface between neurodegeneration and neuroinflammation
Didonna, A. (2020) · Genes & Immunity · doi:10.1038/s41435-020-00113-5 · Cited by 82
Fractalkine/CX3CR1 is involved in the cross-talk between neuron and glia in neurological diseases
Luo, P., Chu, S., Zhang, Z., Xia, C., & Chen, N. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.11.017 · Cited by 90
Liu, W., Jiang, L., Bian, C., Liang, Y., Xing, R., Yishakea, M., & Dong, J. (2016) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-016-0395-9 · Cited by 92
Role of microglia-neuron interactions in diabetic encephalopathy
Liu, Y., Li, M., Zhang, Z., Ye, Y., & Zhou, J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.12.005 · Cited by 88
Cook, C., Kang, S. S., Carlomagno, Y., Lin, W.-L., Yue, M., Kurti, A., Shinohara, M., Jansen-West, K., Perkerson, E., Castanedes-Casey, M., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv336 · Cited by 82
“Moreover, tau pathology is associated with inflammation in both human tissue (28–30) and animal models (24,31,32), suggesting that a toxic interplay between neuroinflammation and tau pathology regulates disease progression.”
BackgroundRecent Advances in the Study of Bipolar/Rod-Shaped Microglia and their Roles in Neurodegeneration
Au, N. P. B., & Ma, C. H. E. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00128 · Cited by 87
“Microglia activation has also been commonly observed in transgenic animal models of AD expressing other forms of mutant tau (Ikeda et al., 2005; Zilka et al., 2009; Bhaskar et al., 2010).”
BackgroundChemokine receptor CXCR2: Physiology regulator and neuroinflammation controller?
Veenstra, M., & Ransohoff, R. M. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.02.016 · Cited by 89
Self-citationMagistri, M., Velmeshev, D., Makhmutova, M., Patel, P., Sartor, G. C., Volmar, C., Wahlestedt, C., & Faghihi, M. A. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160427101832 · Cited by 88
Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury
Gyoneva, S., Kim, D., Katsumoto, A., Kokiko-Cochran, O. N., Lamb, B. T., & Ransohoff, R. M. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0443-0 · Cited by 95
“Specifically, deletion of Cx3cr1 or its ligand Cx3cl1 results in increased tau phosphorylation in mice overexpressing human tau or the APPPS1 model of AD [11, 36, 37].”
BackgroundSelf-citationBassoon proteinopathy drives neurodegeneration in multiple sclerosis
Schattling, B., Engler, J. B., Volkmann, C., Rothammer, N., Woo, M. S., Petersen, M., Winkler, I., Kaufmann, M., Rosenkranz, S. C., Fejtova, A., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0385-4 · Cited by 86
Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction
Raz, L., Bhaskar, K., Weaver, J., Marini, S., Zhang, Q., Thompson, J. F., Espinoza, C., Iqbal, S., Maphis, N. M., Weston, L., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.009 · Cited by 84
Self-citationSimon, E., Obst, J., & Gomez-Nicola, D. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2018.01.059 · Cited by 83
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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