Aquaporin-4 (AQP4) is a water-selective transporter that is predominantly expressed in the central nervous system (CNS), with additional expression in the kidney, lung, stomach, and skeletal muscle. Within the CNS, AQP4 is found in astrocytes and is particularly concentrated at the pial and ependymal surfaces in contact with cerebrospinal fluid (CSF) in the subarachnoid space and ventricles. AQP4 plays a critical role in maintaining water balance in the brain and spinal cord, facilitating the movement of water across cell membranes. AQP4-null mice exhibit phenotypes that suggest the involvement of AQP4 in astrocyte migration, neural signal transduction, and neuroinflammation. These mice show reduced brain swelling in cytotoxic cerebral edema but increased swelling in vasogenic edema and hydrocephalus. AQP4 deficiency also leads to increased seizure duration, impaired glial scarring, and reduced severity of autoimmune neuroinflammation. AQP4 is also implicated in the pathogenesis of neuromyelitis optica (NMO), a neuroinflammatory demyelinating disease. In NMO, autoantibodies (NMO-IgG) target AQP4, leading to astrocyte damage and inflammation. Mice administered NMO-IgG and human complement by intracerebral injection develop characteristic NMO lesions with neuroinflammation, demyelination, perivascular complement deposition, and loss of glial fibrillary acidic protein and AQP4 immunoreactivity.
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