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

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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.

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          Author and article information

          Journal
          J. Neurosci.
          The Journal of neuroscience : the official journal of the Society for Neuroscience
          1529-2401
          0270-6474
          Dec 3 2014
          : 34
          : 49
          Affiliations
          [1 ] Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and Department of Anesthesiology and Peri-Operative Medicine, and Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon 97239 iliffj@ohsu.edu.
          [2 ] Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and.
          [3 ] Department of Anesthesiology and Peri-Operative Medicine, and Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon 97239.
          [4 ] Department of Anesthesiology and Peri-Operative Medicine, and.
          Article
          34/49/16180
          10.1523/JNEUROSCI.3020-14.2014
          25471560
          6d856833-5b2c-4956-b3e9-994008fcbe5b
          Copyright © 2014 the authors 0270-6474/14/3416180-14$15.00/0.
          History

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

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