The role of aquaporin‐4 localization in glymphatic impairment and tau aggregation in post‐traumatic neurodegeneration

Abstract Background Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and has been established as a risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). Neurofibrillary tangles (NFTs), aggregates of intracellular tau, are hallmarks of AD and are observed in the post‐TBI brain; however, the mechanisms that contribute to tau aggregation and accumulation are not well understood. One key mechanism that may contribute to this tau aggregation is decreased clearance by the glymphatic system, a perivascular pathway that clears solutes, including tau, from the brain. Method PS19 mice with tau pathology were crossed with Aqp4 −/− mice lacking the astroglial water channel aquaporin‐4 (AQP4) or Snta1 −/− mice lacking perivascular localization of AQP4. Behavioral tests were performed on the PS19Aqp4 transgenic crosses at 4 months or 6 months of age. Brain tissue was collected and stained for markers of p‐tau pathology. A mild closed‐skull controlled cortical impact TBI model was established and validated. Sham or TBIs were performed on PS19Snta1 transgenic crosses at 3 months of age. Behavioral testing was performed at 4 months (1 month post‐TBI) or 6 months (3 month post‐TBI). Brain tissue was collected and stained for markers of p‐tau pathology. Result We confirmed the previous finding that glymphatic influx is impaired following a closed‐head controlled cortical impact TBI. We also observed that Aqp4 deletion was sufficient to exacerbate tau pathology in PS19 mice at 6 months old, in the absence of TBI, and more advanced tau pathology was observed in PS19 + Snta1 −/‐ mice at 6 months old (3 months post‐TBI) compared to PS19 + Snta +/+ that also received a TBI. Conclusion Loss of AQP4 or loss of perivascular AQP4 promotes tau pathology in a mouse model of tau pathology. These studies may provide a mechanistic basis for the vulnerability of the post‐traumatic brain to tau aggregation and neurodegeneration and suggest that targeting glymphatic dysfunction may be useful in the prevention and treatment of neurodegeneration.