Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration

J Exp Med. 2022 Mar 7;219(3):e20211275. doi: 10.1084/jem.20211275. Epub 2022 Feb 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 4 / deficiency
  • Aquaporin 4 / genetics
  • Aquaporin 4 / metabolism*
  • Brain / metabolism
  • Brain / pathology
  • Extracellular Fluid / metabolism
  • Female
  • Glymphatic System / metabolism*
  • Glymphatic System / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutant Proteins / cerebrospinal fluid
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Protein Aggregation, Pathological / metabolism
  • tau Proteins / cerebrospinal fluid
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Aqp4 protein, mouse
  • Aquaporin 4
  • Mapt protein, mouse
  • Mutant Proteins
  • tau Proteins