Glymphatic system, AQP4, and their implications in Alzheimer's disease

Abstract

Lacking conventional lymphatic system, the central nervous system requires alternative clearance systems, such as the glymphatic system, which promotes clearance of interstitial solutes. Aquaporin-4 water channels (AQP4) are an integral part of this system and related to neuropathologies, such as Alzheimer's disease (AD). The clearance of Alzheimer's associated proteins amyloid β and tau is diminished by glymphatic system impairment, due to lack of AQP4. Even though AQP4 mislocalisation (which affects its activity) is a phenotype of AD, it remains a controversial topic, as it is still unclear if it is a phenotype-promoting factor or a consequence of this pathology. This review provides important and updated knowledge about glymphatic system, AQP4 itself, and their link with Alzheimer's disease. Finally, AQP4 as a therapeutic target is proposed to ameliorate Alzheimer's Disease and other neuropathologies AQP4-related.

Keywords: Alzheimer’s disease; Amyloid-β; Aquaporin-4; Clearance; Glymphatic system.

Fig. 1

Sagittal view of the glymphatic system, showing in detail the astrocytes and their end-feet. CSF flows from the Choroid plexus into the subarachnoid space, under the sagittal sinus. From there, it flows along the outside of brain arteries into the interstitium, mixing with ISF, and clearing the solutes present in the brain parenchyma

Fig. 2

Glymphatic System in Healthy vs AD condition. In healthy condition, CSF flows across highly polarized AQP4 molecules at astrocyte end-feet, mixing with ISF, which allows the clearance of Aβ. However, in pathological situations, such as in AD, there is a loss of AQP4 polarization, resulting in restricted CSF-ISF flow, contributing to Aβ accumulation