Journal
JOURNAL OF NEUROSCIENCE
Volume 34, Issue 49, Pages 16180-16193Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3020-14.2014
Keywords
AQP4; aquaporin-4; cerebrospinal fluid; neurodegeneration; tauopathy; traumatic brain injury
Categories
Funding
- National Institutes of Health-National Institute of Neurological Disorders and Stroke [NS078167, NS078304, NS073373]
- American Heart Association [12SDG11820014]
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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-beta, 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 similar to 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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