Abstract
The brain has high-order functions and is composed of several kinds of cells, such as neurons and glial cells. It is becoming clear that many kinds of neurodegenerative diseases are more-or-less influenced by astrocytes, which are a type of glial cell. Aquaporin-4 (AQP4), a membrane-bound protein that regulates water permeability is a member of the aquaporin family of water channel proteins that is expressed in the endfeet of astrocytes in the central nervous system (CNS). Recently, AQP4 has been shown to function, not only as a water channel protein, but also as an adhesion molecule that is involved in cell migration and neuroexcitation, synaptic plasticity, and learning/memory through mechanisms involved in long-term potentiation or long-term depression. The most extensively examined role of AQP4 is its ability to act as a neuroimmunological inducer. Previously, we showed that AQP4 plays an important role in neuroimmunological functions in injured mouse brain in concert with the proinflammatory inducer osteopontin (OPN). The aim of this review is to summarize the functional implication of AQP4, focusing especially on its neuroimmunological roles. This review is a good opportunity to compile recent knowledge and could contribute to the therapeutic treatment of autoimmune diseases through strategies targeting AQP4. Finally, the author would like to hypothesize on AQP4’s role in interaction between reactive astrocytes and reactive microglial cells, which might occur in neurodegenerative diseases. Furthermore, a therapeutic strategy for AQP4-related neurodegenerative diseases is proposed.
Highlights
We examined the leakage of immunoglobulin G (IgG) to confirm blood-brain barrier (BBB) integrity in an independently established line of AQP4-deficient mice, compared with wild-type (WT) mice, and found that, was the integrity of the BBB maintained in a normal brain, but the recovery of the BBB after breakdown was not altered, even in the absence of AQP4 [14]
Neuromyelitis optica (NMO) is an autoimmune disease consisting of recurrent optic neuritis and transverse myelitis, and serologic testing for the AQP4-immunoglobulin G (IgG) autoantibody is useful for a differential diagnosis from multiple sclerosis (MS) [41,42,43]
AQP4 deletion is directly responsible for Blood-retinal barrier (BRB) dysfunction to the deep plexus capillaries, and strong glial fibrillary acidic protein (GFAP) upregulation was observed in astrocytes in the retina, while the expression of glutamate synthetase (GS), a Müller cell marker, was not observed [76], even though AQP4 was expressed in both types of cells
Summary
Aquaporin 4 (AQP4) is the most abundantly expressed water channel in the brain, and is highly localized in the endfeet of astrocytes (a type of glial cell in the central nervous system (CNS)); these endfeet are in contact with blood vessels [1,2,3]. The inwardly rectifying K+ channel family member, Kir4.1, is co-localized with AQP4 at the endfeet of astrocytes, but not in neurons, to maintain water homeostasis in the CNS. These transmembrane channels seem to play important roles in neurological disorders [8]. ECS shrinkage was most pronounced in the pyramidal cell layer These results imply that AQP4 regulates the dynamics of the extracellular volume
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