Table 1.
AQP4 in different pathological conditions.
| Disease | Mechanism | AQP4 Related Pathology | Rodent Models | (Potential) Therapeutic |
|---|---|---|---|---|
| NMOSD | -AQP4-IgG dependent tissue astrocytophathy: -CDC -ADCC -other mechanisms |
-Presence of AQP4-IgG in serum [44] -Loss of AQP4 in NMOSD lesions [105] -Massive demyelination (brain, optic nerve, spinal cord) [70,75] |
1. Injection of anti-AQP4-IgG into the brain [73] 2. Intravenous injection of AQP4-IgG following BBB disruption through T cell- mediated EAE [59,60], bacterial proteins [67] or anti-endothelial antibody [64]. 3. High affinity circulating rodent AQP4-IgG enter the CNS without BBB impairment [65] |
-Decoy antibody lacking FcR or complement binding [84] -Recombinant IgG1 Fc hexamers that block cytotoxicity and pathological changes [106] |
| Alzheimer’s Disease | Loss of AQP4 polarization with impaired clearance of interstitial solutes and increased aggregation (beta- amyloid) | Mislocalization of AQP4 [13] | AQP4 gene knockout of beta-amyloid precursor protein /presenilin 1 (APP/PS1) transgenic mice [107] | AQP4 receptor agonists [107] |
| ALS | Loss of AQP4 polarization and altered AQP4 expression is contributing to motor neuron degeneration [107] and BBB impairment [108] | AQP4 overexpression in astrocytes [109] | Superoxide dismutase 1 (SOD1) G93A transgenic mice (mouse model of ALS) [109] | Targeting AQP4 as potential treatment to restore BBB in ALS [108] |
| Parkinson’s Disease (PD) | AQP4 dysfunction contributing to synuclein deposition and water accumulation in the substantia nigra [110] | Enriched AQP4-positive astrocytes in the neocortex [111] | AQP4 deficient mice treated with MPTP [112] | N/A |
| Ischemic Stroke | AQP4 enhances edema formation or diminishes resolution | Enhanced expression of AQP4 at site of infarction [10]. | Brain edema caused by acute water intoxication using AQP4 knock out mice [41] | AQP4 inhibitors during edema formation |
| Traumatic brain injury (TBI) | AQP4 is altering water homeostasis and AQP4 may be associated with neuroinflammation (through astrocyte and microglia activation) | Increased expression of AQP4 and loss of AQP4 polarity [9] | TBI mouse model [9] | AQP4 inhibitors may be beneficial [103] |
| Hydrocephalus | Control of water homeostasis | -Increased AQP4 in CSF of congenital communicating hydrocephalus [90], -Hydrocephalus has been reported in AQP4-IgG positive NMOSD [91] | Rat kaolin model [86] | Increasing AQP4 to support CSF clearance at a later disease stage or decreasing AQP4 in areas of CSF production particularly at disease onset [113]. |
| Glioma | -AQP4 is contributing to increased tumor cell migration possibly through increasing water permeability [114]. -Involvement of AQP4 in tumor edema |
Expression of AQP4 in human glioblastoma [115] | N/A | Use of AQP inhibitors to reduce tumor growth [18] |
| Schizophrenia | Reduced AQP4 is contributing to neurovascular dysfunction and BBB hyperpermeability | Astroglial loss and reduced AQP4 expression in the deep layers of the anterior cingulated gyrus [116] | N/A | N/A |
| Major depressive disorder (MDD) | AQP4 is contributing to poor water balance | Reduced coverage of blood vessels by AQP4 positive astrocytic endfeet in the orbitofrontal cortex [117] | N/A | N/A |
| Epilepsy | Impairment of K+ homeostasis | AQP4 expression is increased in samples from atrophic hippocampus from epileptic patients [118] | AQP4 deficient mice [119] | AQP4 modulators to increase seizure thresholds [103] |
| Autism | Abnormal glial-neuronal communication in brains of subjects with autism | Decreased AQP4 expression in cerebellum of post mortem tissue [120] | N/A | N/A |