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Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration
Open accessAbstract
Accumulation of tau has been implicated in various neurodegenerative diseases termed tauopathies. Tau is a microtubule-associated protein but is also actively released into the extracellular fluids including brain interstitial fluid and cerebrospinal fluid (CSF). However, it remains elusive whether clearance of extracellular tau impacts tau-associated neurodegeneration. Here, we show that aquaporin-4 (AQP4), a major driver of the glymphatic clearance system, facilitates the elimination of extracellular tau from the brain to CSF and subsequently to deep cervical lymph nodes. Strikingly, deletion of AQP4 not only elevated tau in CSF but also markedly exacerbated phosphorylated tau deposition and the associated neurodegeneration in the brains of transgenic mice expressing P301S mutant tau. The current study identified the clearance pathway of extracellular tau in the central nervous system, suggesting that glymphatic clearance of extracellular tau is a novel regulatory mechanism whose impairment contributes to tau aggregation and neurodegeneration.
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The glymphatic system is a highly organized, brain-wide network for cerebrospinal fluid transport that exports protein waste, including amyloid and tau.
“The glymphatic system is a highly organized, brain-wide network for cerebrospinal fluid (CSF) transport that exports protein waste, including amyloid and tau1–3.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [3]
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Cites
Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., Benveniste, H., Vates, G. E., Deane, R., Goldman, S. A., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003748 · Cited by 5,824 · cited 6×
“…– brain barrier, phagocytosis by glial cells, receptor-mediated endocytosis by cerebral cells (Rauch et al., 2020; Cooper et al., 2021), and drainage into CSF. ISF drains into CSF via perivascular spaces of cerebral blood vessels by a mechanism termed the glymphatic pathway (Iliff et al., 2012).”
InfluentialSleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411
Structural and functional features of central nervous system lymphatic vessels
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., et al. (2015) · Nature · doi:10.1038/nature14432 · Cited by 4,413
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
Aspelund, A., Antila, S., Proulx, S. T., Karlsen, T. V., Karaman, S., Detmar, M., Wiig, H., & Alitalo, K. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142290 · Cited by 2,198
Transmission and spreading of tauopathy in transgenic mouse brain
Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1901 · Cited by 1,803
Impairment of paravascular clearance pathways in the aging brain
Kress, B. T., Iliff, J. J., Xia, M., Wang, M., Wei, H. S., Zeppenfeld, D., Xie, L., Kang, H., Xu, Q., Liew, J. A., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24271 · Cited by 1,521 · cited 2×
“impaired in aged brain (Kress et al., 2014) and also associated with”
Cerebral Arterial Pulsation Drives Paravascular CSF–Interstitial Fluid Exchange in the Murine Brain
Iliff, J. J., Wang, M., Zeppenfeld, D. M., Venkataraman, A., Plog, B. A., Liao, Y., Deane, R., & Nedergaard, M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1592-13.2013 · Cited by 1,319 · cited 1×
“Cerebral arterial pulsation is a driving force of the glymphatic convective flow (Iliff et al., 2013), which is facilitated by water transport via aquaporin-4 (AQP4) expressed in perivascular astrocyte end-foot processes (Iliff et al., 2012; Mestre et al., 2018).”
Propagation of Tau Misfolding from the Outside to the Inside of a Cell
Frost, B., Jacks, R. L., & Diamond, M. I. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808759200 · Cited by 1,252
The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans
Holth, J. K., Fritschi, S. K., Wang, C., Pedersen, N. P., Cirrito, J. R., Mahan, T. E., Finn, M. B., Manis, M., Geerling, J. C., Fuller, P. M., et al. (2019) · Science · doi:10.1126/science.aav2546 · Cited by 813
Tau Kinetics in Neurons and the Human Central Nervous System
Sato, C., Barthélemy, N. R., Mawuenyega, K. G., Patterson, B. W., Gordon, B. A., Jockel-Balsarotti, J., Sullivan, M., Crisp, M. J., Kasten, T., Kirmess, K. M., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.015 · Cited by 586
Trans-cellular Propagation of Tau Aggregation by Fibrillar Species
Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M., & Diamond, M. I. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.346072 · Cited by 552
LRP1 is a master regulator of tau uptake and spread
Rauch, J. N., Luna, G., Guzman, E., Audouard, M., Challis, C., Sibih, Y. E., Leshuk, C., Hernandez, I., Wegmann, S., Hyman, B. T., et al. (2020) · Nature · doi:10.1038/s41586-020-2156-5 · Cited by 541
Brain-wide glymphatic enhancement and clearance in humans assessed with MRI.
Ringstad, G., Valnes, L. M., Dale, A. M., Pripp, A. H., Vatnehol, S.-A. S., Emblem, K. E., Mardal, K.-A., & Eide, P. K. (2018) · JCI Insight · doi:10.1172/jci.insight.121537 · Cited by 533 · cited 1×
“Glymphatic and lymphatic clearance was first discovered in rodent brains (Iliff et al., 2012; Louveau et al., 2015); however, magnetic resonance imaging studies revealed its presence in the human central nervous system (Eide et al., 2018; Ringstad et al., 2018).”
Flagged first, then by citations
Research works printed but not linked: 27
- Abe, 2020, Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model, Acta Neuropathol. Commun., 8, 67, 10.1186/s40478-020-00936-3 · DOI
- Aoyagi, 2007, Fibrillogenic nuclei composed of P301L mutant tau induce elongation of P301L tau but not wild-type tau, J. Biol. Chem., 282, 20309, 10.1074/jbc.M611876200 · DOI
- Barthélemy, 2020, Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease, J. Exp. Med., 217, 1, 10.1084/JEM.20200861 · DOI · Paper page
- Barthélemy, 2020, A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease, Nat. Med., 26, 398, 10.1038/s41591-020-0781-z · DOI · Paper page
- Burfeind, 2017, The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer’s disease, Alzheimers Dement., 3, 348, 10.1016/J.TRCI.2017.05.001 · DOI · Paper page
- Cao, 2018, Deletion of aquaporin-4 aggravates brain pathology after blocking of the meningeal lymphatic drainage, Brain Res. Bull., 143, 83, 10.1016/j.brainresbull.2018.10.007 · DOI
- Cooper, 2021, Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism, J. Biol. Chem., 296, 100715, 10.1016/j.jbc.2021.100715 · DOI · Paper page
- Eide, 2018, Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes, Sci. Rep., 8, 7194, 10.1038/s41598-018-25666-4 · DOI · Paper page
- Harrison, 2020, Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model, Brain, 143, 2576, 10.1093/brain/awaa179 · DOI · Paper page
- Iba, 2013, Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy, J. Neurosci., 33, 1024, 10.1523/JNEUROSCI.2642-12.2013 · DOI · Paper page
- Ikeshima-Kataoka, 2013, Immunological function of aquaporin-4 in stab-wounded mouse brain in concert with a pro-inflammatory cytokine inducer, osteopontin, Mol. Cell. Neurosci., 56, 65, 10.1016/j.mcn.2013.02.002 · DOI
- Iliff, 2014, Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury, J. Neurosci., 34, 16180, 10.1523/JNEUROSCI.3020-14.2014 · DOI · Paper page
- Da Mesquita, 2018, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease, Nature, 560, 185, 10.1038/s41586-018-0368-8 · DOI · Paper page
- Mestre, 2018, Aquaporin-4-dependent glymphatic solute transport in the rodent brain, Elife, 7, 1, 10.7554/eLife.40070 · DOI · Paper page
- Patel, 2019, Dural lymphatics regulate clearance of extracellular tau from the CNS, Mol. Neurodegener., 14, 11, 10.1186/s13024-019-0312-x · DOI
- Pooler, 2013, Physiological release of endogenous tau is stimulated by neuronal activity, EMBO Rep., 14, 389, 10.1038/embor.2013.15 · DOI · Paper page
- Ringstad, 2017, Glymphatic MRI in idiopathic normal pressure hydrocephalus, Brain, 140, 2691, 10.1093/brain/awx191 · DOI · Paper page
- Tanaka, 2019, Seeding activity-based detection uncovers the different release mechanisms of seed-competent tau versus inert tau via lysosomal exocytosis, Front. Neurosci., 13, 1258, 10.3389/fnins.2019.01258 · DOI
- Wang, 2018, Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies, Acta Neuropathol., 136, 525, 10.1007/s00401-018-1891-2 · DOI
- Wu, 2016, Neuronal activity enhances tau propagation and tau pathology in vivo, Nat. Neurosci., 19, 1085, 10.1038/nn.4328 · DOI · Paper page
- Xu, 2015, Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits, Mol. Neurodegener., 10, 58, 10.1186/s13024-015-0056-1 · DOI · Paper page
- Yamada, 2011, In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice, J. Neurosci., 31, 13110, 10.1523/JNEUROSCI.2569-11.2011 · DOI · Paper page
- Yamada, 2014, Neuronal activity regulates extracellular tau in vivo, J. Exp. Med., 211, 387, 10.1084/jem.20131685 · DOI
- Yamada, 2015, Analysis of in vivo turnover of tau in a mouse model of tauopathy, Mol. Neurodegener., 10, 55, 10.1186/s13024-015-0052-5 · DOI
- Yanamandra, 2013, Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo, Neuron, 80, 402, 10.1016/j.neuron.2013.07.046 · DOI · Paper page
- Yanamandra, 2017, Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy, Sci. Transl. Med., 9, 10.1126/scitranslmed.aal2029 · DOI · Paper page
- Zeppenfeld, 2017, Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains, JAMA Neurol., 74, 91, 10.1001/jamaneurol.2016.4370 · DOI · Paper page
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Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep
Hauglund, N. L., Andersen, M., Tokarska, K., Radovanovic, T., Kjaerby, C., Sørensen, F. L., Bojarowska, Z., Untiet, V., Ballestero, S. B., Kolmos, M. G., et al. (2025) · Cell · doi:10.1016/j.cell.2024.11.027 · Cited by 349
Vojtechova, I., Machacek, T., Kristofikova, Z., Stuchlik, A., & Petrasek, T. (2022) · PLOS Pathogens · doi:10.1371/journal.ppat.1010929 · Cited by 92
Metadata
- Authors
- Ishida, K., Yamada, K., Nishiyama, R., Hashimoto, T., Nishida, I., Abe, Y., Yasui, M., & Iwatsubo, T.
- Affiliations
- The University of Tokyo (JP)
- National Center of Neurology and Psychiatry (JP)
- Keio University (JP)
- Corresponding author
- Yamada, Kaoru
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2022-02-25
- Volume
- 219
- Issue
- 3
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC8932543
- OpenAlex
- W4214574386
- Cited by
- 298
- References
- 14
- Citations by year
- 2026: 90 · 2025: 68 · 2024: 64 · 2023: 60 · 2022: 16
- FWCI
- 17.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Core Research for Evolutional Science and Technology (JPMJCR18H3)
- Japan Agency for Medical Research and Development (JP20dm0207073)
- Grant-in-Aid for Scientific Research (18K07388, 18H02606, 20H00525)
- Niigata University (2021-20012)
- NIPRO Co.
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- glymphatic system, extracellular tau, aquaporin-4, tau clearance, tau aggregation, tauopathy, neurodegeneration, cerebrospinal fluid, deep cervical lymph nodes, P301S tau, tau phosphorylation, brain interstitial fluid
- MeSH terms
- Glymphatic System, Animals, Brain, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, tau Proteins, Mice, Knockout, Extracellular Fluid, Mutant Proteins, Mice, Aquaporin 4, Protein Aggregation, Pathological
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