Enhancing glymphatic transport through angiotensin II type 2 receptor activation promotes neurological recovery after traumatic brain injury.

Background

Traumatic brain injury (TBI) may impair the function of the glymphatic system, leading to diminished metabolic waste clearance and aggravated neurological deficits. While angiotensin II type 2 receptor (AT2R) activation has demonstrated neuroprotective effects, its specific impact on the glymphatic system following TBI remains uncharacterized.

Methods

We utilized near-infrared II (NIR-II) probes with distinct protein-binding capacities to visualize glymphatic transport in TBI mice and investigate how compound 21 (C21)-mediated AT2R activation modulates post-traumatic glymphatic function. Perivascular aquaporin-4 (AQP4) polarization was analyzed by immunofluorescence. RNA sequencing was performed to explore the C21-induced dynamic immune modulation. β-amyloid clearance efficiency and phosphorylated tau accumulation were quantified in mouse brain tissue. Motor and cognitive functions were comprehensively evaluated through standardized behavioral tests.

Results

Our results demonstrate that C21-mediated AT2R activation enhanced glymphatic influx and promoted glymphatic clearance after TBI. Mechanistically, AT2R activation restored perivascular aquaporin-4 (AQP4) polarization and cerebral blood flow, suppressed astrogliosis and microglial activation, and attenuated neuroinflammatory responses. Furthermore, AT2R activation enhanced β-amyloid clearance efficiency and reduced phosphorylated tau accumulation, thereby promoting motor and cognitive functional recovery.

Conclusion

By employing non-invasive or minimally invasive NIR-II imaging, our study highlights the protective effects of AT2R activation on the glymphatic system following TBI, revealing its potential as a promising therapeutic strategy for mitigating TBI-induced damage and improving neurological outcomes.