Multifaceted Roles of Aquaporins in the Pathogenesis of Alzheimer's Disease

Abstract

The central nervous system is highly dependent on water, and disturbances in water homeostasis can have a significant impact on its normal functions. The regulation of water balance is, at least in part, carried out via specialized water channels called aquaporins. In the central nervous system, two major aquaporins (AQPs), AQP1 and AQP4, and their potential involvements have been long implicated in the pathophysiology of many brain disorders such as brain edema and Neuromyelitis optica. In addition to these diseases, there is growing attention to the involvement of AQPs in the removal of waste products in Alzheimer's disease (AD). This indicates that targeting fluid homeostasis is a novel and attractive approach for AD. This review article aims to summarize recent knowledge on the pathological implications of AQPs in AD, discussing unsolved questions and future prospects.

Keywords: Alzheimer’s disease; Aβ; CSF; ISF; aquaporins; glymphatic system; tau.

Figure 1

The aggregation process of Aβ and tau and their release. Aβ is generated from APP after sequential cleavages by β-secretase and γ-secretase and multimerizes into oligomer or protofibril and finally deposits as amyloid plaques. Tau is a microtubule binding protein but becomes detached from microtubules and forms oligomer and deposits as neurofibrillary tangles. Accumulating evidence has now suggested that tau is also released into the extracellular space and therefore a target of extracellular fluid clearance (adapted from “Cleavage of Amyloid Precursor Protein (APP)” and “Pathology of Alzheimer’s Disease” by Biorender.com (accessed on 28 March 2023).

Figure 2

The expression and distribution of AQPs in the brain. (A) AQP4 expressed in perivascular astrocyte endfoot plays a significant role in the glymphatic system that drains Aβ and tau in ISF via the perivascular spaces. (B) AQP4 also has a role in neuronal excitation, and its deficiency may also impact the activity-dependent release of Aβ and tau. (C) AQP1 expressed in the choroid plexus has a role in CSF secretion (adapted from “Cranial meningeas”, “Tripartite Glutamatergic Synapse” and “Rodent Brain Subventricular Zone” by Biorender.com).