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Depletion of microglia and inhibition of exosome synthesis halt tau propagation
Open accessAbstract
Accumulation of pathological tau protein is a major hallmark of Alzheimer's disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus-based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target.
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In the citing paper
“human and microglia can internalise aggregated or hyperphosphorylated tau for protein degradation, they can also release incompletely degraded or un-neutralised forms back it into the extracellular space, promoting the spread of tau [12, 32, 36, 108, 153]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [12]
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
“supporting a preponderant role of microglia in the spread of pathological tau throughout the brain [23,34,35,36].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [34]
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
“microglial elimination from PS19 mice or suppression of inflammation prevents tau-induced neurodegeneration [101–103]”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [101]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The study also showed that inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo.”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [144]
The cited source says what the claim attributes to it.
In the citing paper
“A study by Asai and colleagues demonstrated that exosomes derived from microglia can facilitate the spread of tau protein, another critical pathological hallmark of AD and other tauopathies [144].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [144]
The cited source says what the claim attributes to it.
In the citing paper
“Microglia have also been implicated in the pathological spreading of tau via the release of extracellular vesicles [12, 61, 328]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“Multiple studies have demonstrated that microglia can actively phagocytize tau”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [34]
The cited source says what the claim attributes to it.
In the citing paper
“removing microglia inhibited the spread of tau pathology in an amyloid-free setting [34]”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [34]
The cited source says what the claim attributes to it.
In the citing paper
“Asai and collaborators demonstrated that microglial depletion and exosome synthesis inhibition reduce tau propagation in vivo [34]”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [34]
The cited source says what the claim attributes to it.
In the citing paper
“Conversely, the microglial response to tauopathy appears to drive neurodegeneration.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [101]
The cited source says what the claim attributes to it.
In the citing paper
“This supports a prominent role of microglial activation in tau spread, consistent with previous findings on microglial-derived exosomes47 and NF-κB signaling40.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [47]
The cited source says what the claim attributes to it.
In the citing paper
“Maladaptive microglia are central in pathological tau spread and toxicity40,47.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [47]
The cited source says what the claim attributes to it.
In the citing paper
“Maladaptive microglia play a central role in pathological tau spread and tau toxicity40,59.”
From APOE3 - R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [59]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The deposition of α-syn protein fibrils into larger aggregates such as Lewy bodies or neurites has been associated with strong immunogenic responses in affected tissues of several neurodegenerative diseases (75, 93–97).”
From Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases (2024) · cites this paper as [96]
Experimental — accuracy not yet measuredIn the citing paper
“In addition to effects on modulating tau clearance, microglia may also influence tau propagation through the formation of exosomes, as microglia depletion or inhibition of exosome synthesis can block the propagation of hyperphosphorylated tau [251].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [251]
In the citing paper
“microglia also were implicated in spreading tau aggregates through endocytosis (via phagocytosis) and exocytosis (via exosomes) in a nonsynaptic transmission pathway (68).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [68]
In the citing paper
“Depletion of microglia suppressed tau propagation (68), suggesting that microglia actively contribute to tau pathology during AD pathogenesis.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [68]
In the citing paper
“AD is accompanied by activation of microglia and astrocytes1,2 that affects the clearance and production of Aβ42,3,4 development and propagation of tau pathology,5 exacerbates neurodegeneration, and influences disease progression and severity.6,7”
From CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease (2018) · cites this paper as [5]
In the citing paper
“Inhibition of exosome synthesis using the neutral sphingomyelinase-2 inhibitor reduces tau propagation from the entorhinal cortex to the dentate gyrus in adeno-associated virus (AAV)-based and P301S tauopathy mouse models [80].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [80]
In the citing paper
“Glial cells such as microglia and astrocytes perform normal immune functions in CNS and also play a vital role in the spreading of pathological tau [80, 83].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [80]
In the citing paper
“Asai et al. demonstrated that depleting microglia or inhibiting microglial exosome synthesis reduces tau propagation from the entorhinal cortex to the dentate gyrus in the adeno-associated virus (AAV)/tau-injection P301S tauopathy mice [80] (Fig. 1).”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [80]
In the citing paper
“Studies in a mouse model of tauopathy initiated via viral expression of mutant tau have implicated microglia in the cell-to-cell spread of tau pathology across the brain, possibly mediated by microglial uptake and exosomal release of tau (Asai et al., 2015).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Asai et al., 2015
In the citing paper
“Once engulfed, tau is either degraded [116] or re-released in exocytosing microvesicles called exosomes [7, 55].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [7]
In the citing paper
“Microglia readily take up both soluble and insoluble forms of tau [7, 56, 82, 116].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [7]
In the citing paper
“In contrast, when activated, proinflammatory microglia increase tau phosphorylation50 and drive the spread of tau pathology48.”
From Microglia in neurodegeneration (2018) · cites this paper as [48]
In the citing paper
“Microglia can engulf, degrade, and clear tau48,49.”
From Microglia in neurodegeneration (2018) · cites this paper as [48]
In the citing paper
“Moreover, microglia are pivotal in spreading tau by releasing tau-containing exosomes.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [402]
In the citing paper
“Tau propagation was likely mediated through synaptic connections.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [402]
In the citing paper
“Microglia release tau-containing exosomes that contribute to the spread of tau.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [402]
In the citing paper
“Microglial CSF1R signalling is essential to their survival and has become a thoroughly tested and highly replicated model for targeted elimination of microglia (Elmore et al. , 2014; Asai et al. , 2015; Dagher et al. , 2015; Rice et al. , 2015; Acharya et al. , 2016; Feng et al. , 2016; Spangenberg et al. , 2016; Stafford et al. , 2016; Szalay et al. , 2016; Li et al. , 2017; Bennett et al. , 2018”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Asai et al., 2015
In the citing paper
“Pre-clinical research suggests that microglial activation may precede the formation of tangles47 and then promote the spreading of pathological tau48.”
From Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy (2020) · cites this paper as [48]
In the citing paper
“Depletion of microglia or pharmacological inhibition of exosome secretion led to reduced tau spreading in this model.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Asai et al., 2015
In the citing paper
“Microglial-derived exosomes appear necessary for tau propagation in a model of tau spreading using AAV viral transduced expression of P301Ltau to induce rapid tau spreading from the entorhinal cortex to the dentate gyrus of the hippocampus (Asai et al., 2015).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Asai et al., 2015
In the citing paper
“Fluorescence emitted indicates trafficking of pHrodo-conjugated BDTOs to the acidic lysosomal compartment showing that iMGLs can actively ingest extracellular tau that may be released during neuronal cell death (Villegas-Llerena et al., 2015) and support recent findings that microglia may play a role in tau propagation in AD and other tauopathies (Asai et al., 2015).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Asai et al., 2015
In the citing paper
“Second, recent reports indicate that tau is secreted from neurons and can be taken up by microglia for degradation or transfer to other neurons (Asai et al., 2015; Bolos et al., 2016).”
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 Asai et al., 2015
In the citing paper
“In a tau-spreading mouse model where human P301L tau was focally expressed in medial entorhinal cortex (MEC) layer II/III neurons, microglial cell depletion markedly suppressed tau propagation from the entorhinal cortex to the dentate gyrus by inhibiting microglial secretion of exosomes that contain tau oligomers for seeding57”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [57]
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Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies
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The identity and function of microglia in neurodegeneration
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Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology
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Tau-Targeted Multifunctional Nanocomposite for Combinational Therapy of Alzheimer’s Disease
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“However, microglia can also increase tau propagation, another mechanism of Alzheimer's disease (44).”
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Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
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CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
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Absence of CX3CR1 impairs the internalization of Tau by microglia
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Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
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Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function
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“Microglia have also been implicated in the pathological spreading of tau via the release of extracellular vesicles [12, 61, 328].”
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Activated microglia mitigate Aβ-associated tau seeding and spreading
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Microglial activation and tau burden predict cognitive decline in Alzheimer’s disease
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Intersection of pathological tau and microglia at the synapse
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TREM2 dependent and independent functions of microglia in Alzheimer’s disease
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Targeting microglia for the treatment of Alzheimer’s Disease
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BIN1 favors the spreading of Tau via extracellular vesicles
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P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice
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Metadata
- Authors
- Asai, H., Ikezu, S., Tsunoda, S., Medalla, M., Luebke, J., Haydar, T., Wolozin, B., Butovsky, O., Kügler, S., & Ikezu, T.
- Affiliations
- Boston University (US)
- Universitätsmedizin Göttingen (DE)
- Corresponding author
- Ikezu, Tsuneya
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-10-05
- Volume
- 18
- Issue
- 11
- Pages
- 1584-1593
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4694577
- OpenAlex
- W2190404250
- Cited by
- 1,591
- References
- 63
- Citations by year
- 2026: 105 · 2025: 161 · 2024: 175 · 2023: 159 · 2022: 158 · 2021: 209 · 2020: 166 · 2019: 151 · 2018: 131 · 2017: 89 · 2016: 74 · 2015: 7
- FWCI
- 73.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- GRO (submittedVersion)
- Funders
- National Institute on Aging (R01AG050471, P30AG013846)
- National Institute of Neurological Disorders and Stroke (R01NS089544, R01NS088137)
- National Institute of Environmental Health Sciences (R01ES020395)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- microglia, tau protein, tau propagation, exosomes, Alzheimer's disease, tauopathy, exosome secretion, microglial depletion, entorhinal cortex, dentate gyrus, neuronal excitability, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Male, Mice, Transgenic, Neurons, tau Proteins, Microglia, Entorhinal Cortex, Exosomes
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