Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease
Abstract
:1. Introduction
2. AQP4 and Its Role during Development
3. AQP4 and Its Role in the Adult Brain
Insights from AQP4 Deficient Mice
4. AQP4 during Disease
4.1. Role of AQP4 in Inflammation
Autoantibodies to Astrocytic AQP4 in NMOSD and Its Disease Spectrum
4.2. Role of AQP4 in Controlling Brain-Water Balance
AQP4 and Hydrocephalus
4.3. Role of AQP4 in Glymphatic Clearance, Synaptic Plasticity and Memory
AQP4 and Alzheimer Diseases
5. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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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 |
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Mader, S.; Brimberg, L. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells 2019, 8, 90. https://doi.org/10.3390/cells8020090
Mader S, Brimberg L. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019; 8(2):90. https://doi.org/10.3390/cells8020090
Chicago/Turabian StyleMader, Simone, and Lior Brimberg. 2019. "Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease" Cells 8, no. 2: 90. https://doi.org/10.3390/cells8020090