Gonadal hormones and aquaporin-4: Preclinical insights into glymphatic regulation and amyloid clearance.

Aquaporin-4 (AQP4)-mediated water transport at astrocytic end-feet is pivotal for glymphatic clearance, a process increasingly recognized as a determinant of brain health and resilience to neurodegeneration. Nevertheless, existing literature has not yet systematically clarified how sex hormones influence AQP4 biology and, in turn, glymphatic efficiency, leaving a critical gap in our understanding of sex-specific vulnerability to disorders such as Alzheimer's disease. To address this gap, we investigated how gonadal hormones influence AQP4 expression and polarity within the context of neuroinflammatory processes, drawing on evidence from preclinical models. We conducted a comprehensive review of in vivo and in vitro studies across ischemic stroke, traumatic brain injury, hypoxia-ischemia, osmotic stress, and viral neuroinflammation models, extracting standardized data on hormonal status, AQP4 metrics, neuroinflammatory markers, and fluid-clearance outcomes. The collated findings reveal that loss of estrogen, progesterone, or testosterone amplifies microgliosis, NF-κB activation, cytokine release (IFN-γ, IL-6, IL-8), and AQP4 mislocalization, whereas physiological hormone replacement reverses these changes, restores AQP4 polarity, and stabilizes the blood-brain barrier. These results indicate that sex-dependent regulation of AQP4 and glymphatic flow is a plausible contributor to the higher incidence and faster progression of Alzheimer's disease in postmenopausal women. Our synthesis underscores the need for real-time glymphatic imaging combined with targeted hormonal or anti-inflammatory interventions to determine whether re-establishing proper hormone signaling or AQP4 polarity can slow proteopathic accumulation and modify disease trajectories.