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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Microglia can internalise aggregated or hyperphosphorylated tau for degradation, but can also release incompletely degraded forms into extracellular space, promoting tau spread.
“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]
The Results sections report that microglia engulf aggregated and phosphorylated tau and secrete tau in exosomes, supporting the uptake-and-spread portion of the claim. They do not establish that the tau is internalised for degradation or that the released tau is incompletely degraded; the discussion of failed clearance does not demonstrate either step. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMicroglia have a preponderant role in the spread of pathological tau throughout the brain.
“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]
The Discussion reports that microglia play a significant role in tau propagation, with marked reductions after microglial depletion in two mouse models. The tested spread was in specified brain regions, and the paper also acknowledges other propagation pathways; it does not establish that microglia have a preponderant role throughout the brain. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMicroglial elimination from PS19 mice or suppression of inflammation prevents tau-induced neurodegeneration.
“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]
The Results (‘Depletion of microglia suppresses tau propagation’; page unavailable) show that depleting microglia in PS19 mice reduced phosphorylated tau, and the Discussion says tau propagation and accompanying neurotoxicity were sensitive to microglial depletion. But the PS19 mice were studied before appreciable neuronal loss, so the paper does not show that depletion prevented neurodegeneration. It also reports reduced basal cytokine expression after depletion, not that suppressing inflammation independently prevented neurodegeneration. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo.
“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]
Exosomes derived from microglia can facilitate the spread of tau protein, a critical pathological hallmark of AD and other tauopathies.
“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]
Microglia are implicated in pathological spreading of tau via release of extracellular vesicles.
“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]
Microglia can actively phagocytize tau.
“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]
Removing microglia inhibited the spread of tau pathology in an amyloid-free setting.
“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]
Microglial depletion and exosome synthesis inhibition reduce tau propagation in vivo.
“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 microglial response to tauopathy appears to drive neurodegeneration.
“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]
Microglial activation plays a prominent role in tau spread.
“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]
Maladaptive microglia are central in pathological tau spread and toxicity.
“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]
Maladaptive microglia play a central role in pathological tau spread and tau toxicity.
“Maladaptive microglia play a central role in pathological tau spread and tau toxicity40,59.”
From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [59]
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.
“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]
The Results section ('Depletion of microglia suppresses tau propagation'; page unavailable) discusses microglial responses to tau aggregates, not α-synuclein deposits. The References list names studies of α-synuclein transmission, but our copy does not connect Lewy bodies or neurites with strong immunogenic responses. Searches for α-synuclein, Lewy bodies, and immune responses found no passage addressing the attributed claim. (LLM, conf=0.75)
Experimental — accuracy not yet measuredMicroglia influence tau propagation through formation of exosomes, as microglia depletion or inhibition of exosome synthesis blocks propagation of hyperphosphorylated tau.
“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]
Microglia are implicated in spreading tau aggregates through endocytosis and exocytosis in a nonsynaptic transmission pathway.
“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]
Depletion of microglia suppresses tau propagation, suggesting that microglia actively contribute to tau pathology during Alzheimer's disease pathogenesis.
“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]
AD is accompanied by activation of microglia and astrocytes that affects clearance and production of Aβ, development and propagation of tau pathology, exacerbates neurodegeneration, and influences disease progression and severity.
“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]
Inhibition of exosome synthesis using the neutral sphingomyelinase-2 inhibitor reduces tau propagation from the entorhinal cortex to the dentate gyrus in AAV-based and P301S tauopathy mouse models.
“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]
Glial cells such as microglia and astrocytes perform normal immune functions in the CNS and play a vital role in the spreading of pathological tau.
“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]
Depleting microglia or inhibiting microglial exosome synthesis reduces tau propagation from the entorhinal cortex to the dentate gyrus in AAV/tau-injection P301S tauopathy mice.
“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]
Microglia are implicated in the cell-to-cell spread of tau pathology across the brain in a mouse model of tauopathy initiated via viral expression of mutant tau.
“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
Once engulfed, tau is either degraded or re-released in exosomes.
“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]
Microglia readily take up both soluble and insoluble forms of tau.
“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]
Activated proinflammatory microglia increase tau phosphorylation and drive the spread of tau pathology.
“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]
Microglia can engulf, degrade, and clear tau.
“Microglia can engulf, degrade, and clear tau48,49.”
From Microglia in neurodegeneration (2018) · cites this paper as [48]
Microglia are pivotal in spreading tau by releasing tau-containing exosomes.
“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]
Tau propagation is likely mediated through synaptic connections.
“Tau propagation was likely mediated through synaptic connections.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [402]
Microglia release tau-containing exosomes that contribute to the spread of tau.
“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]
Microglial CSF1R signalling is essential for their survival and has become a thoroughly tested and highly replicated model for targeted elimination of microglia.
“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
Pre-clinical research suggests that microglial activation may precede tangle formation and promote the spreading of pathological tau.
“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]
Depleting microglia or inhibiting exosome secretion reduces tau spreading in that model.
“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
Microglial-derived exosomes are necessary for tau propagation in a P301L tau spreading model.
“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
Fluorescence indicates trafficking of pHrodo-conjugated BDTOs to the acidic lysosomal compartment, showing that iMGLs can actively ingest extracellular tau.
“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
Tau is secreted from neurons and can be taken up by microglia for degradation or transfer to other neurons.
“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 a tau-spreading mouse model where human P301L tau was focally expressed in medial entorhinal cortex 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 seeding.
“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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- 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 · 2014: 1
- 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
- Health Sciences › Medicine › Physiology › 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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