Aquaporin-4 Mediated Glymphatic Dysfunction and Neuroinflammatory Signaling in Neurodegenerative Disorders

Aquaporin channels are the predominant fluid regulating channel found in the central nervous system (CNS) and plays a pivotal role in maintaining fluid and ion homeostasis, as well as regulating neuroinflammation, neurodegeneration, and blood-brain barrier (BBB) disruption. This protein is primarily located at astrocytes endfeet within the blood cerebral barrier and other central nervous system (CNS) junctions, facilitating the movement of water in both directions, buffering potassium levels, and aiding in the clearance of interstitial solutes, along with toxic metabolites such as amyloid-β, via the glymphatic system. Changes in the expression or polarization of AQPs are implicated in neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic stroke. Impaired functionality of AQPs is involved in a number of pathological processes including heightened oxidative stress, disruption of the blood-brain barrier, and neuroinflammation. Such pathways are targeted by transcription factors, including nuclear factor κB (NFκB), and signaling pathways, including p38 MAPK, that increase AQPs expression following the action of stressors. Furthermore, impairment of AQPs polarity suppresses glymphatic clearance and promotes toxic protein accumulation, one of the key features of Alzheimer 's disease. AQPs structural features, including its six transmembrane helices and conserved NPA motifs, are critical for function, positioning it as a putative therapeutic target. Preclinical data support the notion that modulation of AQPs activity may offer neuroprotection through restoration of homeostasis and reduction of inflammation in neurodegenerative disease. This review describes the mechanistic links between AQPs dysfunction and neurodegenerative disease, highlighting its potential and limitations as a therapeutic target for the prevention of CNS disorders.