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

Abstract

AbstractBackgroundTraumatic 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.MethodPS19 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.ResultWe 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.ConclusionLoss 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.