title: Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury.
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.
authors.affiliation: 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.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Iliff
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Plog
authors.affiliation: Department of Anesthesiology and Peri-Operative Medicine, and Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Zeppenfeld
authors.affiliation: Department of Anesthesiology and Peri-Operative Medicine, and.
authors.forename: Melissa
authors.identifier: http://orcid.org/0000-0002-8154-2244
authors.initials: M
authors.lastname: Soltero
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and.
authors.forename: Lijun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and.
authors.forename: Itender
authors.initials: I
authors.lastname: Singh
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and.
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642 and.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics; D001930:Brain Injuries / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D051401:Aquaporin 4; D016875:tau Proteins
keywords: AQP4; aquaporin-4; cerebrospinal fluid; neurodegeneration; tauopathy; traumatic brain injury