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

TLDR

Traumatic brain injury is a known risk factor for early dementia and is associated with neurofibrillary tangles of tau in the post‑traumatic brain. The study aimed to show that extracellular tau is cleared from the brain via paravascular glymphatic pathways in mice. The authors defined the glymphatic system as a brain‑wide network of paravascular channels through which CSF clears interstitial solutes such as amyloid‑β. After TBI, glymphatic function fell by ~60% for at least a month, and loss of aquaporin‑4 worsened this impairment, accelerating tau aggregation and neurodegeneration, indicating chronic glymphatic dysfunction promotes post‑traumatic tau pathology.

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.