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J Neurosci. 2014 Dec 3;34(49):16180-93. doi: 10.1523/JNEUROSCI.3020-14.2014.

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

Author information

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.

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.

KEYWORDS:

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

PMID:
25471560
PMCID:
PMC4252540
DOI:
10.1523/JNEUROSCI.3020-14.2014
[Indexed for MEDLINE]
Free PMC Article

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