AQP4

Aquaporin-4 (AQP4) is a protein that forms water channels in the cell membrane. In humans, it is encoded by the AQP4 gene and is the principal water channel in the central nervous system, where it is highly expressed in astrocyte endfeet that ensheath cerebral blood vessels and in the ependymal lining. It is also detected in some peripheral tissues, but CNS enrichment is a defining feature.

Structure and isoforms: AQP4 forms tetrameric water-permeable pores. It exists mainly as two isoforms, M1 and M23, produced by alternative translation initiation. The M23 isoform tends to assemble into larger supramolecular structures called orthogonal arrays of particles (OAPs) in the plasma membrane. The relative abundance of M1 and M23 influences OAP formation and may affect water permeability and protein interactions.

Function and physiology: AQP4 facilitates rapid water movement in response to osmotic gradients, contributing to brain water homeostasis and cerebrospinal fluid–interstitial fluid exchange. It plays a central role in the glymphatic system, helping coordinate convective water flow along astrocyte endfeet around blood vessels to support waste clearance from the brain.

Clinical significance: Neuromyelitis optica spectrum disorder (NMOSD) is associated with autoantibodies against AQP4 (AQP4-IgG) that bind astrocytic AQP4, leading to astrocyte injury, demyelination, and optic-spinal symptoms. Detection of AQP4-IgG supports diagnosis, and therapies for NMOSD focus on modulating the immune response. Altered AQP4 expression or localization has also been implicated in brain edema after stroke or injury in experimental models, with ongoing research into therapeutic modulation.

Research notes: Animal studies suggest that loss or blockade of AQP4 can reduce edema in some contexts but may worsen outcomes in others, underscoring a complex balance in brain water regulation.