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Featured ArticleArticles, Neurobiology of Disease

Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury

Jeffrey J. Iliff, Michael J. Chen, Benjamin A. Plog, Douglas M. Zeppenfeld, Melissa Soltero, Lijun Yang, Itender Singh, Rashid Deane and Maiken Nedergaard
Journal of Neuroscience 3 December 2014, 34 (49) 16180-16193; https://doi.org/10.1523/JNEUROSCI.3020-14.2014
Jeffrey J. Iliff
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and
2Department of Anesthesiology and Peri-Operative Medicine, and
3Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon 97239
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Michael J. Chen
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and
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Benjamin A. Plog
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and
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Douglas M. Zeppenfeld
2Department of Anesthesiology and Peri-Operative Medicine, and
3Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon 97239
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Melissa Soltero
2Department of Anesthesiology and Peri-Operative Medicine, and
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Lijun Yang
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and
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Itender Singh
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and
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Rashid Deane
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and
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Maiken Nedergaard
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and
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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-β, 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.

  • AQP4
  • aquaporin-4
  • cerebrospinal fluid
  • neurodegeneration
  • tauopathy
  • traumatic brain injury
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The Journal of Neuroscience: 34 (49)
Journal of Neuroscience
Vol. 34, Issue 49
3 Dec 2014
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Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury
Jeffrey J. Iliff, Michael J. Chen, Benjamin A. Plog, Douglas M. Zeppenfeld, Melissa Soltero, Lijun Yang, Itender Singh, Rashid Deane, Maiken Nedergaard
Journal of Neuroscience 3 December 2014, 34 (49) 16180-16193; DOI: 10.1523/JNEUROSCI.3020-14.2014

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Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury
Jeffrey J. Iliff, Michael J. Chen, Benjamin A. Plog, Douglas M. Zeppenfeld, Melissa Soltero, Lijun Yang, Itender Singh, Rashid Deane, Maiken Nedergaard
Journal of Neuroscience 3 December 2014, 34 (49) 16180-16193; DOI: 10.1523/JNEUROSCI.3020-14.2014
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Keywords

  • AQP4
  • aquaporin-4
  • cerebrospinal fluid
  • neurodegeneration
  • tauopathy
  • traumatic brain injury

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