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

Kazuhisa Ishida, Kaoru Yamada, Risa Nishiyama, Tadafumi Hashimoto, Itaru Nishida, Yoichiro Abe, Masato Yasui, Takeshi Iwatsubo

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)


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.

Original languageEnglish
Article numbere20211275
JournalJournal of Experimental Medicine
Issue number3
Publication statusPublished - 2022 Mar 7

ASJC Scopus subject areas

  • General Medicine


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