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

By Jeffrey J. Iliff, Michael J. Chen, Benjamin A. Plog, Douglas M. Zeppenfeld, M. Soltero, Lijun Yang, Itender Singh, R. Deane, Maiken Nedergaard. Journal of Neuroscience, 2014

951 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Epidemiology, Neurology

View Paper: https://www.semanticscholar.org/paper/b6d58c7360f0530f55609e8361ef086b604fb829

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Anne Sofie Finmann Munk
2. Maiken Nedergaard
3. I. Lundgaard
4. Nadia Aalling Jessen
5. M. Sofroniew

In Neurology

1. A. Louveau
2. Maiken Nedergaard
3. Tajie H. Harris
4. Jonathan Kipnis
5. M. Sofroniew

Citations in the corpus

• The Glymphatic System – A Beginner's Guide (2015, positive): “Traumatic brain injury is linked to formation of large astroglial scars and persistent activation of innate neuroinflammation [122].”
• Revisiting the concept of CNS immune privilege (2015, background): “Interestingly, the glymphatic system appears to be impaired in mice deficient in water-channel aquaporin-4 (Aqp4), suggesting a role for this molecule, which is expressed on astrocyte endfeet [42], in the bulk diffusion of water in the brain [34,40,41].”