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

Dec 5, 2014The Journal of neuroscience : the official journal of the Society for Neuroscience

Reduced waste clearance in the brain may increase tau protein buildup after traumatic brain injury

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Abstract

Glymphatic pathway function was reduced by approximately 60% after traumatic brain injury (TBI) and remained impaired for at least one month.

Extracellular tau is cleared from the brain along paravascular pathways.
Impairment of glymphatic function after TBI may contribute to tau aggregation.
Genetic deletion of the aquaporin-4 gene worsened glymphatic dysfunction following TBI.
The exacerbation of glymphatic pathway dysfunction is associated with increased neurofibrillary pathology and neurodegeneration.
Chronic glymphatic impairment after TBI could increase the risk of developing dementia.

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

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