Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain
Open accessAbstract
Pathological aggregation of tau is a hallmark of Alzheimer’s disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1−/− mice. Second, CD45+ microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1−/− mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret®) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain. Neuroinflammation accelerates tau pathology, but the role played by microglia is uncertain. Maphis et al. provide direct evidence that reactive microglia are sufficient to drive hyperphosphorylation and aggregation of tau protein in a cell-autonomous manner, and show that microglial activation correlates with the spread of tau pathology in mice.
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Microglia activation precedes tau aggregation and promotes tau hyperphosphorylation, subsequently leading to formation of NFTs.
“since activation of microglia precedes tau aggregation41 and promotes tau hyperphosphorylation which subsequently leads to the formation of NFTs.42”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [42]
The Introduction reports that microglial activation precedes tau pathology in a P301S mouse model, and the Results show that reactive microglia induce tau hyperphosphorylation and early aggregation. The Results describe pre-tangle aggregates but do not establish that the induced hyperphosphorylation subsequently led to mature neurofibrillary tangles. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCytokines released by microglia trigger specific intraneuronal signaling that causes tau seeding and hyperphosphorylation.
“cytokines released by microglia trigger specific intraneuronal signaling that causes tau seeding and hyperphosphorylation [37,38].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [38]
The Discussion (page unavailable) suggests that IL1B from activated microglia drives tau pathology and identifies neuronal IL-1R–p38 MAPK signaling. The Results (page unavailable) show microglia-induced tau hyperphosphorylation that is reduced by blocking IL-1 signaling. The paper reports early tau aggregation and possible spread, but does not establish that this cytokine-driven signaling causes tau seeding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMicroglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 MAPK in the hTau mouse model of tauopathy deficient for microglial fractalkine receptor CX3CR1.
“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 [23]
The Introduction reports that CX3CR1 deficiency in hTau mice increased microglial activation, accelerated tau pathology, and impaired working memory; it says mechanistic studies suggested involvement of IL-1R–p38 MAPK signaling. The Results also report that blocking IL-1 signaling reduced microglia-induced tau hyperphosphorylation alongside reduced p38 MAPK activation. The paper does not establish the cited sentence’s p38α-specific mechanism or show that cognitive impairment occurs via that pathway. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAdoptive transfer of reactive microglia from hTau-Cx3cr1 -/- mice led to induction of tau hyperphosphorylation and aggregation within the brains of recipient mice, which was also mediated via the IL-1β-p38α MAPK signaling pathway.
“In a recent study, we demonstrated that adoptive transfer of reactive microglia from hTau-Cx3cr1 –/– mice led to induction of tau hyperphosphorylation and aggregation within the brains of recipient mice, which was also mediated via the IL-1β–p38α MAPK signaling pathway [23].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [23]
The Discussion reports that transferred hTauCx3cr1−/− microglia induced tau phosphorylation and ‘pre-tangle-type’ aggregation in recipient brains. The Results show that an IL-1 receptor antagonist reduced tau hyperphosphorylation and p38 MAPK activation, supporting the proposed pathway. The paper does not identify the p38α isoform specifically or establish that this pathway mediates the aggregation finding. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCX3CR1 deficiency impairs microglia-mediated tau internalization in vitro and promotes accumulation of hyperphosphorylated tau in vivo.
“CX3CR1 deficiency impairs microglia-mediated tau internalization in vitro, and promotes the accumulation of hyperphosphorylated tau in vivo [263, 429].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [429]
Microglia activation induces tau hyperphosphorylation via the IL-1β/p38α MAPK pathway in vitro and in vivo.
“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 [135]
Deletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments.
“Deletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition [130–132] but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments [132–137] (Fig. 1).”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [135]
p38α MAPK is a key kinase involved in microglia-induced neuroinflammation leading to tau pathology, and this kinase can also directly regulate tau phosphorylation.
“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 [135]
Deleting the microglial protein Cx3cr1 in transgenic tau models genetically enhanced microglial activation and accelerated the onset and progression of tau pathology.
“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 Maphis et al., 2015
The exacerbation of tau pathology in Cx3cr1 knockout mice was blocked with IL-1 antagonists.
“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 Maphis et al., 2015
The observations in CX3CR1-deficient htau mice corresponded with a reduction in synaptosome associated protein 25 and learning and memory deficits.
“These observations corresponded with a reduction in synaptosome associated protein 25, critical for synaptic vesicle fusion, as well as learning and memory deficits.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [137]
Adoptive transfer of microglia from CX3CR1−/− htau mice into non-transgenic recipients resulted in increased AT8 p-tau staining and p-38-MAPK signaling, which was blocked by co-injection with an IL-1R agonist.
“adoptive transfer of microglia from CX3CR1−/− htau mice into non-transgenic recipients resulted in increased AT8 p-tau staining and p-38-MAPK signaling which was blocked by co-injection with an IL-1R agonist [137].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [137]
In young CX3CR1-deficient htau mice, increased microgliosis and IL-1β levels appeared to precede tau pathology, accelerate p38-MAPK activation and p-tau accumulation, and result in reduced hippocampal weight in aged mice.
“another group also reported increased microgliosis and IL-1β levels in young CX3CR1 deficient htau mice which appeared to precede tau pathology, accelerate p38-MAPK activation and p-tau accumulation, and result in reduced hippocampal weight in aged mice [137].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [137]
Genetic ablation of Cx3cl1 or Cx3cr1 in mouse models of tauopathy enhances tau hyperphosphorylation, tau pathology, neuroinflammation, and cognitive deficits via the IL-1/p38 MAPK pathway.
“Genetic ablation of Cx3cl1396,397 or Cx3cr1389,398 in mouse models of tauopathy enhanced tau hyperphosphorylation, tau pathology, neuroinflammation, and cognitive deficits389,396–398 via IL-1/p38 MAPK pathway.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [398]
Deleting the microglial cell-expressed homeostatic gene Cx3cr1 in htau mice leads to amplified microglial activation and enhanced tau hyperphosphorylation/aggregation.
“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 [63]
The correlation between inflammation and tangle formation has also been noted in other tauopathies, such as frontotemporal dementia and chronic traumatic encephalopathy.
“The correlation between inflammation and tangle formation has also been noted in other tauopathies, such as frontotemporal dementia and chronic traumatic encephalopathy [42–45].”
From Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease (2018) · cites this paper as [44]
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BIN1 favors the spreading of Tau via extracellular vesicles
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Self-citationThe <scp>NLRP3</scp> inflammasome modulates tau pathology and neurodegeneration in a tauopathy model
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Microglia: Friend and foe in tauopathy
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Self-citationRetromer dysfunction at the nexus of tauopathies
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TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo
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“For instance, cytokines released by microglia trigger specific intraneuronal signaling that causes tau seeding and hyperphosphorylation [37,38].”
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- Authors
- Maphis, N., Xu, G., Kokiko-Cochran, O. N., Jiang, S., Cardona, A., Ransohoff, R. M., Lamb, B. T., & Bhaskar, K.
- Affiliations
- University of New Mexico (US)
- Cleveland Clinic (US)
- The University of Texas at San Antonio (US)
- Biogen (United States) (US)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-03-31
- Volume
- 138
- Issue
- 6
- Pages
- 1738-1755
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4542622
- OpenAlex
- W2088685810
- Cited by
- 595
- References
- 78
- Citations by year
- 2026: 51 · 2025: 59 · 2024: 80 · 2023: 55 · 2022: 73 · 2021: 59 · 2020: 48 · 2019: 50 · 2018: 50 · 2017: 36 · 2016: 24 · 2015: 10
- FWCI
- 29.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000439)
- National Institute on Aging (R01AG023012, AG023012)
- National Institute of General Medical Sciences (SC1GM095426, GM095426-02)
- National Institute of Neurological Disorders and Stroke (RF1NS083704, R21NS077089, NS074804, R01NS083704, R01NS074804)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- reactive microglia, tau pathology, tau hyperphosphorylation, tau aggregation, Alzheimer's disease, tauopathy, CX3CR1, microglial activation, neuroinflammation, tau propagation, spatial memory impairment, hippocampus, adoptive transfer, interleukin-1 receptor antagonist
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Brain, Hippocampus, Humans, Memory Disorders, Phosphorylation, tau Proteins, Microglia, Mice, Knockout, Receptors, Chemokine, Tauopathies, Mice, Interleukin 1 Receptor Antagonist Protein, Primary Cell Culture, Protein Aggregates
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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