Aquaporin 4 knockdown alleviates traumatic brain edema and reduces neuronal axonal growth cone collapse via the RhoA/ROCK pathway.

The pathogenesis of secondary brain edema following Traumatic Brain Injury (TBI) is closely associated with the expression of Aquaporin 4 (AQP4). The increase in activated astrocytes after TBI constitutes the cellular basis for AQP4 upregulation, while simultaneously leading to post-TBI glial scar formation, which impairs neuronal axonal repair and neuronal survival. However, the mechanism by which AQP4 overexpression-induced edema affects neuronal repair remains to be elucidated. Therefore, this study aims to modulate AQP4 expression to elucidate its impact on brain edema following TBI and its neuroprotective effects. In this experiment, we confirmed that reducing AQP4 expression helps alleviate brain edema in TBI mice and mitigates neuronal loss and damage in the pericontusional edema zone. Importantly, longitudinal DTI-MRI scanning results demonstrated that modulating AQP4 expression exerted significant neuroprotective effects during both the acute and chronic phases of TBI, effectively rescuing neurological deficits in TBI mice. Mechanistically, this study revealed through scRNA-seq that reduced AQP4 expression significantly decreased Sema3A secretion from astrocytes. This reduction mitigated neuronal axon terminal growth cone collapse via the RhoA-ROCK pathway, thereby promoting neuronal survival. Collectively, this research elucidates how attenuated AQP4 expression in astrocytes mitigates TBI-induced brain edema and facilitates nerve fiber repair, while identifying underlying mechanisms influencing neuronal axons. These findings provide new evidence supporting AQP4 as a potential clinical therapeutic target.