Impaired glymphatic system is associated with secondary neuronal injury in the thalamus following cerebral cortical infarction

Focal cerebral infarction leads to abnormal amyloid-β (Aβ) deposits, which relates to secondary neuronal injury in the ipsilateral thalamus and hinders post-stroke functional recovery. However, the mechanisms underlying Aβ-pathology in the thalamus remain unclear. This study was designed to investigate the potential associations of glymphatic system with Aβ deposits and delayed neuronal damage of the ipsilateral thalamus secondary to cerebral infarction. Cortical infarction was induced with middle cerebral artery occlusion (MCAO). Secondary neuronal damage, Aβ deposits and aquaporin 4 (AQP4) polarity in the thalamus were examined by Nissl staining, immunochemistry and immunoblotting analyses. Glymphatic function was evaluated using fluorescent tracers. The effects of glymphatic system on Aβ deposits and secondary neuronal damage were determined by shRNA-mediated AQP4 knockdown. The results showed that AQP4 polarization and the clearance of tracers were obviously decreased in the ipsilateral thalamus at seven days after MCAO when compared to the sham-operated group. In parallel, there were increases in Aβ deposits, neuronal loss and astrogliosis in the ipsilateral thalamus at seven days after MCAO. Additionally, AQP4 knockdown further reduced the degree of AQP4 polarity and efflux function of tracers, coinciding with marked increases in Aβ deposits and neuronal loss in the ipsilateral thalamus at seven days after MCAO. This effect was associated with exacerbated somatosensory and cognitive deficits. These findings suggest that impaired glymphatic system was associated with secondary neuronal damage in the thalamus after cerebral infarction by possibly suppressing Aβ clearance.