Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury

Jeffrey Iliff, Michael J. Chen, Benjamin A. Plog, Douglas M. Zeppenfeld, Melissa Soltero, Lijun Yang, Itender Singh, Rashid Deane, Maiken Nedergaard

Research output: Contribution to journalArticle

278 Scopus citations

Abstract

Traumatic brain injury (TBI) is an established risk factor for the early development of dementia, including Alzheimer’s disease, and the post-traumatic brain frequently exhibits neurofibrillary tangles comprised of aggregates of the protein tau. We have recently defined a brain-wide network of paravascular channels, termed the “glymphatic” pathway, along which CSF moves into and through the brain parenchyma, facilitating the clearance of interstitial solutes, including amyloid-b, from the brain. Here we demonstrate in mice that extracellular tau is cleared from the brain along these paravascular pathways. After TBI, glymphatic pathway function was reduced by ~60%, with this impairment persisting for at least 1 month post injury. Genetic knock-out of the gene encoding the astroglial water channel aquaporin-4, which is importantly involved in paravascular interstitial solute clearance, exacerbated glymphatic pathway dysfunction after TBI and promoted the development of neurofibrillary pathology and neurodegeneration in the post-traumatic brain. These findings suggest that chronic impairment of glymphatic pathway function after TBI may be a key factor that renders the post-traumatic brain vulnerable to tau aggregation and the onset of neurodegeneration.

Original languageEnglish (US)
Pages (from-to)16180-16193
Number of pages14
JournalJournal of Neuroscience
Volume34
Issue number49
DOIs
Publication statusPublished - Dec 3 2014

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Keywords

  • AQP4
  • Aquaporin-4
  • Cerebrospinal fluid
  • Neurodegeneration
  • Tauopathy
  • Traumatic brain injury

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Iliff, J., Chen, M. J., Plog, B. A., Zeppenfeld, D. M., Soltero, M., Yang, L., ... Nedergaard, M. (2014). Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. Journal of Neuroscience, 34(49), 16180-16193. https://doi.org/10.1523/JNEUROSCI.3020-14.2014