The infiltration of blood components into the brain parenchyma through the lymphoid system is an important cause of
subarachnoid hemorrhage injury. AQP4, a
water channel protein located at the astrocyte foot, has been reported to regulate blood-brain barrier integrity, and its polarization is disrupted after SAH. Neuronal ferroptosis is involved in
subarachnoid hemorrhage- (SAH-) induced
brain injury, but the inducing factors are not completely clear.
Transferrin is one of the inducing factors of ferroptosis. This study is aimed at researching the role and mechanism of AQP4 in
brain injury after
subarachnoid hemorrhage in mice. An experimental mouse SAH model was established by endovascular perforation. An AAV vector encoding AQP4 with a GFAP-specific promoter was administered to mice to achieve specific overexpression of AQP4 in astrocytes. PI staining, Fer-1 intervention, and transmission electron microscopy were used to detect neuronal ferroptosis, and
dextran (40 kD) leakage was used to detect BBB integrity. Western blot analysis of perfused brain tissue
protein samples was used to detect
transferrin infiltration. First, neuronal ferroptosis 24 h after SAH was observed by PI staining and Fer-1 intervention. Second, a significant increase in
transferrin infiltration was found in the brain parenchyma 24 h after SAH modeling, while
transferrin content was positively correlated with neuronal ferroptosis. Then, we observed that AQP4 overexpression effectively improved AQP depolarization and BBB injury induced by SAH and significantly reduced
transferrin infiltration and neuronal ferroptosis after SAH. Finally, we found that AQP4 overexpression could effectively improve the neurobehavioral ability of SAH mice, and the neurobehavioral ability was negatively correlated with
transferrin brain content. Taken together, these data indicate that overexpression of AQP4 in the mouse brain can effectively improve post-SAH neuronal ferroptosis and
brain injury, at least partly by inhibiting
transferrin infiltration into the brain parenchyma in the glymphatic system.