Astrocytic PEN-2 Governs Cerebral Edema via Autophagic Control of AQP4 Homeostasis

Cerebral edema, a life-threatening consequence of central nervous system (CNS) injury, lacks effective therapies. Aquaporin-4 (AQP4), the main water channel in astrocytes, plays critical roles in both the formation and resolution of edema, with unclear regulatory mechanisms. Here, we uncover a ?-secretase-independent function of presenilin enhancer 2 (Pen-2) in AQP4 turnover. Conditional Pen-2 inactivation in astrocytes results in metabolic alterations, severe cerebral edema and early lethality. Mechanistically, Pen-2 physically interacts with AQP4 to promote its degradation through the autophagy-lysosome pathway. Treatment with acetazolamide, an AQP4 inhibitor, reverses the edema phenotype in Pen-2-deficient mice, establishing AQP4 as a critical downstream effector. This study unveils a previously unrecognized Pen-2-AQP4 axis that governs brain water homeostasis and reveals a promising therapeutic target for edema treatment. Overall design: RNA-seq profiling of wildtype and Pen-2 cKO mice cortex at P8.