Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo
Open accessAbstract
The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons—a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer’s disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein.
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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 [32]
The Discussion (page not provided) reports evidence that microglia internalize and degrade insoluble pathological tau, and the paper demonstrates microglial uptake of tau. It does not say that microglia release incompletely degraded tau or thereby promote its spread; its discussion of extracellular tau release concerns cell lines and neurons. (LLM, conf=0.88)
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 [35]
The Abstract reports that microglia internalize tau in vitro and in vivo, and the Discussion proposes that increasing microglial clearance of extracellular tau could help arrest tau pathology. These passages support a role for microglia in handling tau, but do not establish that they have a preponderant role in spreading pathological tau throughout the brain. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia 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 [35]
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 [82]
Tau inclusions have been reported in microglia despite a lack of tau expression, providing evidence that pathological tau may transfer between cells in the brain.
“Tau inclusions have also been reported in microglia [80–82] despite a lack of tau expression, providing further evidence that pathological tau may also be transferring between cells in the brain.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [82]
Microglia can engulf, degrade, and clear tau.
“Microglia can engulf, degrade, and clear tau48,49.”
From Microglia in neurodegeneration (2018) · cites this paper as [49]
Microglia could phagocytize different tau species, and this process was partly dependent on the microglial fractalkine receptor CX3CR1.
“Microglia could phagocytize different tau species,386,387 and this process was partly dependent on microglial fractalkine receptor (CX3CR1) receptor.388”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [387]
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 Bolos et al., 2016
Insoluble tau isolated from postmortem Alzheimer's disease brain is taken up by microglia in vitro and in vivo.
“Insoluble tau isolated from postmortem Alzheimer’s disease brain is shown to be taken up by microglia in vitro and in vivo56.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [56]
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Lee-Gosselin, A., Jury-Garfe, N., You, Y., Dabin, L., Soni, D., Dutta, S., Rochet, J.-C., Kim, J., Oblak, A. L., & Lasagna-Reeves, C. A. (2023) · Cells · doi:10.3390/cells12121597 · Cited by 19 · see citing works
- Authors
- Bolós, M., Llorens-Martín, M., Jurado-Arjona, J., Hernández, F., Rábano, A., & Avila, J.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Fundacion Centro De Investigacion De Enfermedades Neurologicas (ES)
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2016-01-12
- Volume
- 50
- Issue
- 1
- Pages
- 77-87
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2195638710
- Cited by
- 234
- References
- 46
- Citations by year
- 2026: 10 · 2025: 24 · 2024: 38 · 2023: 26 · 2022: 25 · 2021: 44 · 2020: 22 · 2019: 16 · 2018: 18 · 2017: 9 · 2016: 2
- FWCI
- 12.07
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Alzheimer's Association
- Comunidad de Madrid
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Instituto de Salud Carlos III
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, microglia
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Animals, Animals, Newborn, Calcium-Binding Proteins, Cells, Cultured, Cerebral Cortex, Glial Fibrillary Acidic Protein, Hippocampus, Humans, Mice, Inbred C57BL, Microfilament Proteins, Phosphorylation, Time Factors, tau Proteins, Microglia, Protein Transport, Mice, Rats
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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