Aquaporin-4 and Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia. Although the pathogenesis of AD remains unclear, AD is thought to result from an imbalance in the production and clearance of amyloid-β protein (Aβ). Aquaporin-4 (AQP4) is the major aquaporin in the mammalian brain, is mostly expressed on astrocytic endfeet, and functions as a water transporter. However, the distribution and expression of AQP4 are altered in both AD clinical populations and animal models. Recent studies have revealed that AQP4 is important to the clearance of Aβ in brain via lymphatic clearance, transcytotic delivery, and glial degradation, as well as to the synaptic function. Thus, AQP4 likely plays an important role in the pathogenesis of AD. Further studies would provide new targets for prevention, ultimately leading to improved treatment options for AD.

Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

“…Recent findings suggest that the brain lymphatic system contributes to clearing the majority of extracellular Aβ from the brain . The cerebral lymphatic system consists of two parts: glymphatic system in the brain parenchyma and lymphatic networks located in the dura mater .…”

“…These two systems seem to play a synergetic role in driving Aβ out of the brain, with each alteration potentially influencing the AD process . Suppression of glymphatic fluid transport has been observed in APP/PS1 transgenic AD model mice, with glymphatic malfunction seen prior to presence of substantial Aβ deposits .…”

Does sleep disturbance affect the amyloid clearance mechanisms in Alzheimer's disease?

“…36 Moreover, there have been interesting studies during recent years evaluating the distribution and expression of Aqp4 in preclinical and clinical AD studies. 37 In this context, experimental studies have already shown the role of Aqp4-dependent trans-astrocytic ISF bulk flow in the clearance of Aβ through the glymphatic system. 24,37,38 These results were confirmed with subsequent studies using Aqp4-knockout mice showing reduced A 40 clearance that resulted in Aβ deposition in the cortex and hippocampus.…”

“…37 In this context, experimental studies have already shown the role of Aqp4-dependent trans-astrocytic ISF bulk flow in the clearance of Aβ through the glymphatic system. 24,37,38 These results were confirmed with subsequent studies using Aqp4-knockout mice showing reduced A 40 clearance that resulted in Aβ deposition in the cortex and hippocampus. 32 Although there are no actual data indicating the modulatory role of sleep-wake cycles on the Aqp4 expression, awakened mice showed much-decreased clearance of exogenously applied Aβ from the interstitial space that was significantly reversed during sleep.…”

“…Studies in the last decade have already shown the pivotal role of astrocytes in ‘cleaning the brain’ through the glymphatic pathway and indicate the specific modulatory role of astrocytic Aqp4 expression during the sleep . Moreover, there have been interesting studies during recent years evaluating the distribution and expression of Aqp4 in preclinical and clinical AD studies . In this context, experimental studies have already shown the role of Aqp4‐dependent trans‐astrocytic ISF bulk flow in the clearance of Aβ through the glymphatic system .…”