Citation: Municio, C.; Carrero, L.;
Antequera, D.; Carro, E. Choroid
Plexus Aquaporins in CSF
Homeostasis and the Glymphatic
System: Their Relevance for
Alzheimer’s Disease. Int. J. Mol. Sci.
2023, 24, 878. https://doi.org/
10.3390/ijms24010878
Academic Editor: Hongjun
(Harry) Fu
Received: 18 November 2022
Revised: 27 December 2022
Accepted: 27 December 2022
Published: 3 January 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
 International Journal of 
Molecular Sciences
Review
Choroid Plexus Aquaporins in CSF Homeostasis and the
Glymphatic System: Their Relevance for Alzheimer’s Disease
Cristina Municio 1,2, Laura Carrero 1,2, Desireé Antequera 2,3 and Eva Carro 2,3,*
1 Group of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12),
28041 Madrid, Spain
2 Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII,
28031 Madrid, Spain
3 Neurobiology of Alzheimer’s Disease Unit, Functional Unit for Research into Chronic Diseases,
Instituto de Salud Carlos III, 28222 Madrid, Spain
* Correspondence: eva.carro@isciii.es; Tel.: +34-918223995
Abstract: The glymphatic system, a fluid-clearance pathway involved in brain waste clearance,
is known to be impaired in neurological disorders, including Alzheimer’s disease (AD). For this
reason, it is important to understand the specific mechanisms and factors controlling glymphatic
function. This pathway enables the flow of cerebrospinal fluid (CSF) into the brain and subsequently
the brain interstitium, supported by aquaporins (AQPs). Continuous CSF transport through the
brain parenchyma is critical for the effective transport and drainage of waste solutes, such as toxic
proteins, through the glymphatic system. However, a balance between CSF production and secretion
from the choroid plexus, through AQP regulation, is also needed. Thus, any condition that affects
CSF homeostasis will also interfere with effective waste removal through the clearance glymphatic
pathway and the subsequent processes of neurodegeneration. In this review, we highlight the role of
AQPs in the choroid plexus in the modulation of CSF homeostasis and, consequently, the glymphatic
clearance pathway, with a special focus on AD.
Keywords: aquaporins; choroid plexus; cerebrospinal fluid; glymphatic system; Alzheimer’s disease;
astrocytes; clearance; homeostasis
1. Introduction
Protein aggregates are a common feature of neurodegenerative diseases, including
Alzheimer’s disease (AD) [1]. This implies that reduced brain clearance, which results in the
accumulation of anomalous proteins, could be a shared phenomenon in neurodegeneration.
Cerebrospinal fluid (CSF), the main component of the extracellular fluid in the central
nervous system (CNS), is a vital pathway for waste clearance from the neural tissue [2,3].
Analytical studies of CSF molecules have revealed that they can act as biomarkers for the
diagnosis of clearance failure from the CNS in diseases such as AD.
Along perivascular spaces, CSF transport partly involves the metabolic waste disposal
pathway in the brain known as the “glymphatic system” [4]. The glymphatic system works
as a waste drainage pathway comprising a perivascular network for CSF transport [4,5],
and is connected to the lymphatic system, associated with dura covering the brain as well
as cranial nerves and large vessels at the skull exits [6,7]. The processes of these structures
are intricate and only partly understood.
In the glymphatic pathway, a convective CSF influx is compensated by the perive-
nous efflux of the interstitial fluid (ISF), clearing noxious proteins and peptides, including
amyloid-beta (Aβ) [4]. CSF movement into the parenchyma, facilitated by aquaporins
(AQPs), drives the convective ISF fluxes within the tissue toward the perivenous spaces [4].
The consequent CSF transport into the brain parenchyma is mainly facilitated by AQP4 wa-
Int. J. Mol. Sci. 2023, 24, 878. https://doi.org/10.3390/ijms24010878 https://www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2023, 24, 878 2 of 17
ter channels, which are expressed in a polarized way in the astrocytic end-feet surrounding
the brain vasculature [4,8].
In the last decade, several studies reported that soluble Aβ protein and tau oligomers
are removed from the brain through the glymphatic system [4,9–12]. These emerging find-
ings prove promising for the development of novel therapeutic targets for the prevention
of AD pathogenesis. In this review, we address recent findings on CSF and the glymphatic
system, with a special interest in the role of the choroid plexus and AQP expression, to
provide insights into the mechanisms underlying this complex clearance system.
2. Choroid Plexus
To maintain the extracellular environment of the brain, the blood–brain barrier (BBB)
and the blood–CSF barrier (BCSFB) separate the blood from the brain parenchyma and the
CSF, respectively [13]. The BCSFB is primarily composed of the choroid plexus epithelial
cells that are connected by tight junctions restricting access to the brain parenchyma [14]
(Figure 1). The remainder of the BCSFB is composed of the arachnoid membrane and
circumventricular organs. The mammalian choroid plexus is a highly vascularized secretory
tissue localized in the brain ventricles [15]. The choroid plexus tissue includes a monolayer
of epithelial cells surrounding the connective tissue with fenestrated capillaries inside. The
apical membrane of the choroid plexus epithelium is covered by microvilli, which increase
the membrane area in contact with the intraventricular space. Microvilli primarily consist
of cilia and motile cilia, with sensory and motile functions, respectively [16].
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 2 of 17 
 
 
by AQP4 water channels, which are expressed in a polarized way in the astrocytic end-
feet surrounding the brain vasculature [4,8]. 
In the last decade, several studies reported that soluble Aβ protein and tau oligomers 
are removed from the brain through the glymphatic system [4,9–12]. These emerging find-
ings prove promising for the development of novel therapeutic targets for the prevention 
of AD pathogenesis. In this review, we address recent findings on CSF and the glymphatic 
system, with a special interest in the role of the choroid plexus and AQP expression, to 
provide insights into the mechanisms underlying this complex clearance system. 
2. Choroid Plexus 
To maintain the extracellular environment of the brain, the blood–brain barrier (BBB) 
and the blood–CSF barrier (BCSFB) separate the blood from the brain parenchyma and 
the CSF, respectively [13]. The BCSFB is primarily composed of the choroid plexus epithe-
lial cells that are connected by tight junctions restricting access to the brain parenchyma 
[14] (Figure 1). The remainder of the BCSFB s composed of the arachnoid membrane and 
ircumventricular organs. The mammalian choro d plexu  is a highly vascularized secre-
tory tissue localiz d in th  brain ventricles [15]. The chor id plexus tissue includes a mon-
olayer of epithelial cells surrounding the connective tissue with fenestrated capillaries in-
s de. The apical membra e of the choroid plexus epith lium i  covere  by icr villi, 
which increase the membrane area in contact with the intraventricular space. M crovilli 
primarily consist  cilia and motile cilia, with sensory and motile functions, respectively 
[16]. 
 
Figure 1. Illustration of choroid plexus epithelial cells (left) and tight junctions at the luminal mem-
brane (right). CP: choroid plexus; CSF: cerebrospinal fluid; JAMs: junctional adhesion molecules; 
ZO: zonula occludens. 
The choroid plexus epithelial cells are sealed by tight junctions at the luminal mem-
brane conferring the barrier property to the BCSFB. Tight junctions are composed of pro-
teins associated with the cell membrane of the choroid plexus epithelial cells [17–19]. Oc-
cludin was the first tight junction protein to be reported in the choroid plexus [20]. An-
other group of tight junction proteins is claudins, divided into several subtypes, among 
which claudin 1–6, 9–12, 19, and 22 are expressed in the choroid plexus epithelial cells 
Figure 1. Illustration of choroid plexus epithelial cells (left) and tight junctions at the luminal
membrane (right). CP: choroid plexus; CSF: c rebrospinal fluid; JAMs: j ti al ad sion molecules;
ZO: zonula occludens.
The choroid plexus epithelial cells are sealed by tight junctions at the luminal mem-
brane conferring the barri r property to the BCSFB. Tight junctions are composed of prot ins
associated with the cell m mbran of he choroid plexus epithelial cells [17–19]. Occludin
was the first ight junction protein to be report d in the choroid plexus [20]. Another group
of tight junction proteins is claudins, divided into several subtypes, among which claudin
1–6, 9–12, 19, and 22 are expressed i the choroid plexus epithelial cells [21], limiting the
through-p t of tight junction [22]. Zonula occludens (ZO) protein is another tig t junction
protein in the cuboidal choroid plexus epithelial cells [23]. Three ZO proteins, namely
ZO1, ZO2, and ZO3, bind occludin and claudin to actin filaments [24]. Junctional adhesion
molecules (JAMs) are tight junction proteins that have been implicated in the epithelial
Int. J. Mol. Sci. 2023, 24, 878 3 of 17
barrier function [23] (Figure 1). They have short cytoplasmic tails to bind to proteins such
as ZO1, cingulin, and occludin, which allows the formation of multiprotein complexes with
tight junctions [25,26].
The major function of the choroid plexus is to form the BCSFB and produce the
CSF. For this purpose, the plasma that flows through the fenestrated capillaries is rapidly
transported by hydrostatic pressure into the choroid plexus interstitium. Once filtered by
the membranous diaphragms, the ultrafiltrate is transported through the choroid plexus
epithelial cells to the ventricle, where it can be used in CSF production [27].
Contrary to other secretory epithelia, in the choroid plexus epithelium, most ion
transporters are located in the apical membrane, for example, Na+-K+ ATPase channels,
K+-Cl-Na+HCO3 cotransporters, or some AQP water channels. Only a few transporters,
such as K+Cl- cotransporters, are found on the basolateral membrane [28]. In addition, in
recent decades, other functions have been associated with the choroid plexus such as the
modulation of CSF composition, CNS development, and regeneration, the removal of waste
and metabolites, brain immunosurveillance, or circadian rhythmicity regulation [29–36].
Several significant alterations have been indicated in the aging choroid plexus. A
loss of 11% in the volume of human choroid plexus epithelial cells has been associated
with aging. In addition to collagen fibers and dystrophic calcifications within the stroma,
aged choroid plexus epithelial cells show increased pathological protein deposits called
Biondi ring tangles [37,38]. Reduced glucose metabolism and energy production have been
observed in the choroid plexus of aging rats [39]. Furthermore, the accumulation of toxic
products and lipofuscin, a product of lipid peroxidation, indicates higher oxidative stress
in the aging choroid plexus [40].
Morphological changes in the choroid plexus have been described in AD, including
the atrophy of choroid plexus epithelial cells with the accumulation of lipofuscin vacuoles,
stromal fibrosis, and the thickening of blood vessel walls and the basement membrane of the
choroid plexus [41–44]. Larger choroid plexus volume was associated with the severity of
cognitive impairment in the AD spectrum [45]. These structural and molecular alterations
in the choroid plexus lead to impairment of the BCSFB that may result in changes in CSF
composition in the AD brain [13,46–49]. Increasing lines of evidence suggest that choroid
plexus dysfunction could be a major factor contributing to AD pathogenesis [46,50,51].
Aβ accumulation in the choroid plexus affects its structure and function. We and others
demonstrated that Aβ deposition in the choroid plexus of AD patients results in impaired
physiological functions of the choroid plexus epithelium, such as a decrease in mitochon-
drial activity, oxidative stress, and morphological/structural alterations [46,52–56].
Aβ presence in the choroid plexus may induce innate immune reactions, increasing
the concentration of IgG that leads to capillary damage and interstitial fibrosis [57]. It
has previously been reported that the expression of type I and II interferons, involved in
the recruitment of immune cells to the CNS, is altered in the choroid plexus in AD [58].
In the early stages of AD, the presence of Aβ can increase the secretion of proinflam-
matory cytokines (IL-1, IL-6, and TNF-α) and matrix metalloproteinases, leading to the
downregulation of tight junction proteins and thus BCSFB dysfunction [46].
It is well known that the primary role of the BCSFB is to prevent the free passage of
molecules between the blood and the CSF, and the main function of the choroid plexus
is to the production and regulation of the CSF [2,14,27,59]. However, this specialized
tissue is also involved in neuroimmune surveillance, as immune cell exchange between the
blood and the CSF occurs at the choroid plexus level [34–36]. The choroid plexus manages
immune cell recruitment into the CNS under several pathological situations, including
AD [60]. Many studies have shown an increase in the number of immune cells in the
choroid plexus and the CSF following immune challenges to the CNS [61–64]. A variety
of immune cells, including macrophages, basophils, mast cells, dendritic cells, monocytes,
neutrophils, and lymphocytes, are present in the choroid plexus [65]. However, choroid
plexus macrophages are the most abundant immune cells [64]. Notably, the immunological
network preserves the immune surveillance of the CNS from outside the parenchyma,
Int. J. Mol. Sci. 2023, 24, 878 4 of 17
and under pathological conditions, it contributes to neuroinflammation. This reaction is
believed to be mediated by the choroid plexus, which serves as a selective gateway for
leukocyte entry [34].
Inflammation is an important defensive response to infection or injury, and the choroid
plexus is known as an entry site for pathogens, a checkpoint for peripheral immune cells into
the CNS, and a regulator of cytokines and other signaling molecules in the CSF [58,66,67].
Specifically, TNF-α signaling is induced in the choroid plexus of AD patients and AD
mouse models [68].
Additionally, the choroid plexus is involved in the control of circadian rhythmicity [31–33].
The behavioral circadian rhythm is an integrated output of multiple brain clocks, for which
the choroid plexus is an essential element. Indeed, the presence of a circadian clock in the
choroid plexus has been associated with a robust circadian gene expression rhythm [31].
The circadian rhythmicity of choroid plexus clock genes differs with sex, exhibiting more
diurnal differences in female rats than in male rats [69]. It is established that estradiol
impacts the expression of clock genes, modulated by the estrogen receptor [69]. More
recently, we revealed the dysregulation of circadian rhythmicity in the choroid plexus of a
mouse model with AD [70].
3. Glymphatic System
In 2012, Nedergaard and colleagues defined the glymphatic system as a network of
perivascular spaces through which the CSF circulates in the brain parenchyma [4]. The
glymphatic system involves the entry of subarachnoid CSF into the brain parenchyma
through periarterial spaces, after which it mixes with parenchymal ISF and interstitial
waste products, facilitated by the AQP4 water channels located in astrocytic end-feet,
and drains through the perivenous spaces surrounding the veins (Figure 2) [4]. The
glymphatic pathway is a highly organized fluid transport system and has a three-step
serial process. First, the CSF flows from the subarachnoid space into the brain through
the perivascular spaces of large leptomeningeal arteries; then, it is driven into the brain
parenchyma through the perivascular spaces of the penetrating arteries. This movement
is facilitated by the positive CSF pressure from the choroid plexus and the arterial pulse
caused by the cardiac cycle. Afterward, the CSF flows across the basal membrane and
astrocytic end-feet, bordering the brain parenchyma, where AQP4 contributes to the CSF
flow into the parenchyma, mixing with the ISF [4,7,71]. The CSF and ISF are in continuous
exchange, and both are cleared together with solutes. The flux passes from the interstitium
into specific perivenous pathways and is drained through a meningeal lymphatic vessel,
thus reaching the cervical lymphatic system [4,72].
It is well documented that the CSF and the cerebral ISF drain into deep cervical lymph
nodes, but the CSF also drains into the perineural space. In fact, perineural pathways along
the optic and olfactory nerves are considered relevant lymphatic routes [73,74]. However, it
remains unknown whether waste solutes are mainly cleared through perineural drainage,
thus traveling along the cranial nerves, or drain into the nerve itself. Although more
studies are needed, it has been reported that the CSF and waste solutes predominantly
drain directly into lymphatic vessels along the exiting cranial nerves and not directly into
the venous circulation [7].
Most neurodegenerative diseases are characterized by the improper accumulation of
cellular waste products, among which misfolded proteins are the most difficult to clear
from the brain, and their aggregates lead to diseases such as AD [5]. The glymphatic
system has been recently discovered as an alternative waste clearance system enabling
the removal of soluble proteins and metabolites from the CNS [4,71]. The designation of
the glymphatic clearance pathway refers to its appropriation of the lymphatic function for
interstitial protein management and its dependence on glial water transport [75].
Int. J. Mol. Sci. 2023, 24, 878 5 of 17I t. J. ol. Sci. 2023, 24, x FOR PEER REVIEW 5 of 17 
 
 
 
Figure 2. Brain lymphatic drainage system. (A) Glymphatic system clears solutes and waste of the 
brain parenchyma due to the influx of CSF from the periarterial space. Once the CSF is mixed with 
the ISF, they drain into the perivenous space. Part (B) shows a summary of the other brain drainage 
systems that transport the CSF through the meningeal lymphatic vessels and/or perineural path-
ways, such as olfactory nerve, to the cervical lymph nodes AQP: aquaporin; CNS: central nervous 
system; CSF: cerebrospinal fluid; ISF: interstitial fluid. 
Most neurodegenerative diseases are characterized by the improper accumulation of 
cellular waste products, among which misfolded proteins are the most difficult to clear 
from the brain, and their aggregates lead to diseases such as AD [5]. The glymphatic sys-
tem has been recently discovered as an alternative waste clearance system enabling the 
removal of soluble proteins and metabolites from the CNS [4,71]. The designation of the 
glymphatic clearance pathway refers to its appropriation of the lymphatic function for 
interstitial protein management and its dependence on glial water transport [75]. 
Although the best-described function of the glymphatic system is solute clearance, 
studies are underway on other possible functions such as facilitating the transport of glu-
cose [76], apolipoprotein E (ApoE) [77] or lipids [78]. The BBB restricts the influx of lipids 
and lipoproteins into the brain. Internal lipid transport occurs through the secretion of 
lipoproteins by astrocytes, mainly apolipoproteins. These carriers are central for the 
preservation of brain homeostasis, as they mediate the clearance of excess cholesterol and 
Aβ, and their deficiency is a risk factor for AD [79]. Part of the ApoE production occurs in 
the choroid plexus of the third ventricle, which is directly secreted into the CSF [77]. 
Therefore, glymphatic transport pathways contribute to the distribution of ApoE into the 
brain [77]. 
Glymphatic activity decreases with advanced age. Studies in mice show a reduction 
in the efficiency of clearance and loss of perivascular APQ4 polarization in the astrocytes 
of aging mice compared with young mice [80]. AQP4 is localized in the astrocytic end-feet 
of young animals; however, the polarization of these water channels is reduced in aging 
Fi re . rai l atic rainage s ste . ( ) ly phatic syste clears solutes and aste of t e
brai are c y a e t t e i fl f fr t i rt ri l . ce the SF is ixe it
t e ISF, t i i t t i . rt ( ) s s a s ar of the other brain drainage
syste s that transport the CSF through the meningeal lymphatic vessels and/or perineural pathways,
such as olfactory nerve, to the cervical lymph nodes AQP: aquaporin; CNS: central nervous system;
CSF: cerebrospinal fluid; ISF: interstitial fluid.
Although the best-described function of the glymphatic system is solute clearance,
studies are underway on other possible functions such as facilitating the transport of
glucose [76], apolipoprotein E (ApoE) [77] or lipids [78]. The BBB restricts the influx of
lipids and lipoproteins into the brain. Internal lipid transport occurs through the secretion
of lipopr teins y astrocytes, mainly apolipoproteins. These carriers are central f r t e
preserv tion of brain homeostasis, as they mediate the clearance of excess cholester l and
Aβ, and their deficiency is a risk factor for AD [79]. Part of the ApoE pr duction occurs
in the c roid pl xu of the third ven ricle, w ich is directly secreted into he CSF [77].
Ther fore, glymph tic transport pathways ontrib te to the d str bution of ApoE into the
brain [77].
Glymphatic activity decreases with advanced age. Studie in mice show a reducti n
in the efficienc of clearance and oss of perivascular APQ4 polarization in the astrocytes
of aging mice compared with young mice [80]. AQP4 is localized in the astrocytic e -
feet of young animals; however, the p larization of these water channels is reduced i
aging reactive astrocytes, c a acterized by rea tive gl osis [80]. With advanc d age, CSF
production decreases, alo g with the stiffening of th arterial walls, leading to a reduction
in glymphatic activity [81].
It has been establishe that the glymphatic system is more effective during sleep and is
largely inactive during wakefulness [11,82,83]. During sleep, the brain’s extracellular space
is enlarged, thus reducing resistance to fluid flow and promoting more CSF infiltration in
perivascular spaces [84,85]. Based on these findings, the sleep cycle enables more effective
CSF clearance in the glymphatic system by eliminating the metabolic waste generated
Int. J. Mol. Sci. 2023, 24, 878 6 of 17
during wakefulness. Thus, interruptions in the sleep cycle would functionally impair
glymphatic clearance, resulting in defective waste removal and the potential accumulation
of neurotoxic elements such as Aβ [11,86–88]. This finding is in line with the previously
reported findings showing that sleep deficiency significantly raises Aβ levels, thus increas-
ing its deposition [89]. Coincidentally, most AD patients suffer from circadian rhythm
disorders [90–92]. Therefore, improvement in the sleep quality of AD patients could be
a potential therapeutic approach by helping recovery or at least preventing pathological
evolution.
The glymphatic system is one of the numerous mechanisms that contribute to the
removal of soluble Aβ from the brain [93]. AD patients display altered CSF dynamics,
potentially causing an imbalance in the production and clearance of soluble Aβ, resulting
in the accumulation of Aβ in the brain [94]. Additionally, cerebral Aβ deposition was
associated with arterial stiffness, which contributes to a disruption of vascular dynamics
and complicates the perivascular flow of Aβ [95]. This results in a detrimental cycle in
which Aβ deposition along the blood vessels impairs the glymphatic function and promotes
more severe Aβ accumulation in the parenchyma and ultimately neuronal death.
AQP4, located on the perivascular astrocytic end-feet, enables the exchange of CSF
and ISF and facilitates CSF influx into the brain parenchyma and its efflux back to the
perivascular space [96]. Owing to the findings of Iliff and colleagues, who revealed a
decrease in CSF influx and glymphatic function due to AQP4 knockout, it is now estab-
lished that the functionality of the glymphatic system highly relies on AQP channels [4].
Nevertheless, several of the key structural and functional aspects of the glymphatic system
are still debated [97], including whether it involves a convective flow or a passive diffusion
process [86]. However, AQP4 is not the only factor involved in the glymphatic system;
AQP1 also has a significant role in ISF and CSF homeostasis [98–100].
4. Aquaporins
AQPs are a heterogeneous group of channel-forming proteins found in all kingdoms of
life [101]. AQPs are small transmembrane proteins that mediate the transport of water and
some small non-charged molecules, such as glycerol, sugars, or gases, through the plasma
membrane. This process is driven by solute and osmotic gradients [102]. To date, 13 types
of AQPs (AQP0-12) have been identified that, besides having permeability features, enable
specific subcellular and tissue localization, which suggests an association between the
function and site of expression [103]. They are divided into two main categories, classical
and non-classical. Classical AQPs, namely AQP0, AQP1, AQP2, AQP4, AQP5, AQP6, and
AQP8, are involved in water permeability. This group also includes aquaglyceroporins, i.e.,
AQP3, AQP7, AQP9, and AQP10, which support the transport of some neutral solutes and
glycerol, in addition to water. Superaquaporins, or non-classical AQPs, include AQP11
and AQP12. The role of these AQPs has not yet been identified since their physiological
function contributing to water permeability is not yet clarified [104].
AQPs are tetramers and comprise monomers with identically hydrophilic membrane
proteins. Each monomer includes six transmembrane alpha helix segments and two
short helix segments, joined by five connecting loops. The carboxyl and terminal amino
domains are located on the intracellular side. This distribution allows AQPs to operate
as a hydrophilic integral membrane protein [105]. The central pore is composed of two
consensus motifs of asparagine–proline–alanine (NPA) in the short segment. The presence
of AQPs in biological membranes is regulated by exocytosis and endocytosis [106].
The distribution of AQPs includes different organs and tissues, which have been
associated with a variety of important physiological functions including brain water home-
ostasis, transepithelial fluid transport, osmoregulation, angiogenesis, wound healing, cell
signaling, migration, and proliferation [107,108]. In addition, AQPs have been suggested
as potential targets for drug development [103].
In the brain, AQPs mediate the movement of water between different fluid com-
partments, including the CSF, the ISF, and the blood [109,110]. As recently reported by
Int. J. Mol. Sci. 2023, 24, 878 7 of 17
Trillo-Contreras and colleagues, nine AQPs have been identified in different sites of the
CNS: AQP1, AQP3, AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, and AQP11 (Table 1) [111].
Table 1. Distribution of aquaporins in brain’s tissues. Modified from Trillo et al., 2022 [111].
Protein Tissue Expression References
AQP1
Eye, choroid plexus, circumventricular
organs, astrocytomas, sensory neurons of
dorsal root, trigeminal and nodose ganglia
[112–124]
AQP3 Eye, astrocytes, neurons [125]
AQP4
Subpial astrocyte end-feet, retina, neurons,
circumventricular organs, hippocampus,
ependymal cells, glial cells, Purkinje cells,
choroid plexus
[122,126–129]
AQP5 Astrocytes, neurons, choroid plexus [111,118,120,125,130,131]
AQP6 Cerebellum [132]
AQP7 Brain development, choroid plexus [133,134]
AQP8 Astrocytes, neurons, oligodendrocytes,astrocytomas [125,135]
AQP9 Substantia nigra, tanycytes, astrocytes, spinalcord radial astrocytes [131,134,136,137]
AQP11 Choroid plexus [138,139]
5. AQPs in Choroid Plexus and Their Role in Glymphatic System
The expression of AQPs has not been extensively studied in the choroid plexus;
however, there is evidence that AQP1, AQP4, AQP5, AQP7, and AQP11 are expressed in
the epithelial cells of the choroid plexus.
AQP1 was observed on the choroid plexus epithelial cells of mice, where it is lo-
cated in the apical membrane at the ventricular-facing surface of the choroid plexus
epithelium [112–118,127,140,141]. The choroid plexus of aging rats showed lower lev-
els of AQP1 expression, with decreased secretory activity [14]. Moreover, AQP1 expression
was also characterized in the primary human plexus epithelial cells [119–121]. The main
site of AQP1 expression is in the apical membrane domain, although in some cells, a
low basolateral expression has also been detected [128]. AQP1 is a cGMP-gated cation
channel [142,143], and functions as a water channel and a gated ion channel in the choroid
plexus, contributing to the regulation of CSF production [98,109,144,145]. Based on ex-
perimental findings using AQP1 null mice, it is estimated that AQP1 participates in CSF
production, generating between 20% and 25% CSF [115]. Importantly, in an AD triple
transgenic mouse model, AQP1 expression was found to be reduced in the choroid plexus
epithelial cells in parallel with reduced CSF production [146]. However, no significant
change in AQP1 expression was observed in the choroid plexus of AD patients [48]. There-
fore, more investigations are needed on human choroid plexus tissue, and age and disease
comparisons should be further investigated. However, the potential impact of AQP1 on
CSF/ISF homeostasis, including CSF production and drainage, CSF/ISF exchange, and the
consequent CSF-mediated clearance systems, is unquestionable.
In the CNS, the most frequent aquaporin is AQP4. It is usually expressed in ependymal-
glial-limiting membranes, including the ependymal cells and subependymal glia that
border the brain ventricles, in the subpial astrocytes of the cortex, the end-feet of the
perivascular astrocytes that surround the blood vessels forming the BBB, and the choroid
plexus. The presence of AQP4 in the choroid plexus of rats was reported in some previ-
ous studies, in which they showed weak and diffuse AQP4 signals [122,126]. However,
AQP4 overexpression in the choroid plexus is markedly promoted by hypoxia, contribut-
ing to the increase in CSF production observed under hypoxic events [140], but also by
hypertension [127].
AQP4-positive cells were found in the choroid plexus of human donors, where the
AQP4 signal was mostly observed in the basolateral membrane domain [128]. In this recent
Int. J. Mol. Sci. 2023, 24, 878 8 of 17
study, AQP4 mRNA levels were also present and increased in older mice, which suggests an
association between advanced age and increased AQP4 expression, and therefore it could
act as a compensatory mechanism to preserve CSF levels and reduce its production [128].
In a previous study by Iliff et al., it was found that AQP4, expressed in astrocytic
end-feet in contact with the brain vasculature, facilitates CSF transport into the brain
parenchyma [4]. The authors showed a drastic reduction in both CSF fluid flux through
the mouse parenchyma and the clearance of intrastriatal-injected radio-labeled Aβ by
genetic ablation of AQP4 in astrocytes [4]. Therefore, the perivascular glymphatic pathway,
driven by AQP4-dependent bulk flow, has been proposed as the main clearance pathway
of interstitial fluid solutes from the brain parenchyma [8].
Although the dependence of the glymphatic system on AQP4 has been demonstrated
and reported in some studies [147], the physiological mechanism by which AQP4 at
astrocyte end-feet facilitates glymphatic flux is not yet completely understood. Subcellular
relocalization of AQP4, from intracellular vesicles to the plasma membrane, is critical in
the modulation of AQP4 function, being a dynamic process independent of changes in
AQP4 expression [148–150]. AQP4 is mainly found on astrocytic end-feet, allowing its
contact with the perivascular space adjacent to the blood vessels, facilitating CSF influx
and its efflux back to the perivascular space. AQP4 connects astrocyte cytoplasm with
the ISF, allowing a dynamic fluid that facilitates interstitial movement, essential for the
glymphatic flow [4]. Since AQP4 is also localized in choroid plexus epithelial cells as the
basolateral level [128], AQP4 is implicated in other aspects of CSF homeostasis. It has
been suggested that the choroid plexus epithelial cells express AQP4 to modulate CSF
production, generating a higher transcellular waterflow that leads to normal waterflow and
CSF production [128]. It was reported that CSF distribution is under circadian control and
that AQP4 supports this circadian rhythm [151]. Thus, the expression and functionality of
AQP4 in the choroid plexus are directly essential for maintaining regular CSF production
and the consequent glymphatic activity. Alterations in any of the components, including
AQP4, of this multifactorial pathway, may lead to an impaired glymphatic waste clearance
function causing the accumulation of waste and neurotoxic proteins (e.g., Aβ, tau) which
contribute to neurodegenerative diseases. Reduced perivascular AQP4 expression has been
reported in the frontal cortical gray matter of subjects with AD compared to cognitively
intact subjects. This AQP4 decrease was associated with increasing Aβ and neurofibrillary
pathological burden, and with cognitive decline prior to dementia onset [152]. In addition to
the well-described role of astrocytic AQP4, we believe that choroid plexus AQP4 expression
may change with physiological and pathological conditions, with the following effects on
glymphatic clearance activity that may contribute to the development of neurodegenerative
diseases, including AD.
AQP5 has been also described in choroid plexus epithelial cells [118]. Moreover, with
apical epithelial cell localization, AQP5 mRNA expression and protein levels were upreg-
ulated during posthemorrhagic ventricular dilatation [120]. Although AQP5 localization
has been described in choroid plexus [118,120], its role on CSF homeostasis has not been
demonstrated. However, its expression has been associated with brain edema [130]. A
recent study has described the relationship between changes in AQP expression or distribu-
tion with ischemia, commonly associated with edema [111]. In other tissues such as salivary
glands and the eye, AQP5 is involved in the production of primary saliva and tear forma-
tion, respectively, and their secretory regulation [153]. Other studies reported that AQP5,
expressed in human salivary glands occasioned a significant rise in the osmotically directed
net fluid [154], and AQP5 knockout results in reduced water secretion. AQP5 expression
also influences the transepithelial water flux along the respiratory segments [155]. Thus,
we suggest that AQP5 downregulation may lead to a reduction in CSF secretion seriously
affecting the CSF/ISF homeostasis and the consequent glymphatic clearance system.
The aquaglyceroporin AQP7 mRNA and protein levels were largely found in the
choroid plexus, increasing during perinatal development of the brain, and suggesting
that AQP7 could be an important structural and functional element in the choroid plexus
Int. J. Mol. Sci. 2023, 24, 878 9 of 17
during brain development in mice [133]. Evidence of AQP7 in the apical membrane of
the choroid plexus cells implies probable cooperation between AQP7 and AQP1 in CSF
excretion [122,156]. However, these studies are not conclusive and these results would
need to be confirmed.
AQP7 was first denoted as “aquaporin adipose” because it was initially described
in human adipose tissue [157]. Next, other researchers found AQP7 expression in other
tissue, including the choroid plexus [133,134]. Although the AQP7 role is mainly associated
with fat metabolism, it is reported that APQ7 is directly involved in water transport in
adipocytes [158]. AQP7-knockout mice were shown to develop reduced water permeability
in the kidney [159]. Nevertheless, the role of AQP7 at the choroid plexus, as well as in the
CSF secretion, requires further studies.
In rat choroid plexus a weak AQP11 expression has been reported [138]. More recently,
AQP11 localization in the epithelium was confirmed in mouse brains [139]. At this time, the
function of AQP11 at the BBB in water permeability is not well understood, thus its role in
the choroid plexus remains unknown. AQP11 has been identified in intracellular organelles
in different cell types, mainly in the endoplasmic reticulum [160]. Due to its intracellular
location, its role in the transport of water and/or other solutes is still debated. Several
studies have provided questionable data about AQP11 transport specificity [138,160], but
other studies using in vivo and in vitro permeability assays, exposed that AQP11 may act
as a functional water channel [161–163].
6. Conclusions
Although the choroid plexus is involved in the production and regulation of one of the
central components of the glymphatic system, the CSF, not enough attention has been paid
to research on the glymphatic system. A balance between CSF production and drainage
is required for operative waste removal through the clearance glymphatic pathway. In
this environment, AQPs play a major role in CSF homeostasis. As we propose in Figure 3,
impairments in choroid plexus functioning in AD, including AQPs expression and function,
could directly disturb the glymphatic system’s efficiency, with the corresponding pernicious
effects in the neuropathological processes driving AD.
The choroid plexus comprise an intricate network of complexly organized cells that, in
addition to functioning as a barrier between the blood and CSF, have now been confirmed to
play a major role in neurological processes, including AD. Currently, more understanding
about the connection between the choroid plexus and glymphatic system is appearing,
and in this review, we summarized some key elements to contribute highlight the role of
AQPs in the choroid plexus modulating CSF homeostasis and, consequently, the clearance
glymphatic pathway.
Int. J. Mol. Sci. 2023, 24, 878 10 of 17
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 10 of 17 
 
 
 
Figure 3. Relationship between choroid plexus and glymphatic system. In healthy conditions 
(above), the choroid plexus forms the BCSFB and produces CSF. CSF flows from the periarterial 
space to the brain parenchyma via AQP4, located in the end-feet of astrocytes. This movement is 
favored positive pressure of CSF production from the choroid plexus and the arterial pulse. The 
CSF/ISF mixture and waste products are cleared by passing into the perivenous space to be taken 
to the lymphatic tissues. In AD (below) the expression of AQPs decreases in choroid plexus epithe-
lial cells causing a reduction in CSF production. The decrease in pressure exerted by the CSF to-
gether with the diminution and depolarization of AQP4 in the astrocyte end-feet, reduces the glym-
phatic function, preventing a correct clearance of the ISF and waste products. AQP: aquaporin; 
BCSFB: brain CSF barrier; CSF: cerebrospinal fluid; CP: choroid plexus; ISF: interstitial fluid. 
Author Contributions: Conceptualization, C.M. and E.C.; investigation, C.M, L.C. D.A. and E.C.; 
resources, C.M, L.C. D.A. and E.C.; writing—original draft preparation, C.M. and E.C.; writing—
review and editing, C.M. and E.C.; funding acquisition, E.C. All authors have read and agreed to 
the published version of the manuscript. 
Funding: This study was supported by grants from CIBERNED (CB07/502, PI2021/03) and Funda-
cion Española para la Investigación en Parkinson (2020/0123). 
Institutional Review Board Statement: Not applicable. 
Informed Consent Statement: Not applicable. 
Data Availability Statement: Data is contained within the article. 
Conflicts of Interest: The authors declare no conflict of interest. 
  
Figure 3. Relationship between choroid plexus and glymphatic system. In healthy conditions (above),
the choroid plexus forms the BCSFB and produces CSF. CSF flows from the periarterial space to the
brain parenchyma via AQP4, located in the end-feet of astrocytes. This movement is favored positive
pressure of CSF production from the choroid plexus and the arterial pulse. The CSF/ISF mixture and
waste products are cleared by passing into the perivenous space to be taken to the lymphatic tissues.
In AD (below) the expression of AQPs decreases in choroid plexus epithelial cells causing a reduction
in CSF production. The decrease in pressure exert d by the CSF together with t e diminution and
depolarization of AQP4 in the astrocyte end-feet, reduces the glym hatic function, preventing a
correct clearance of the ISF and waste products. AQP: aquaporin; BCSFB: brain CSF barrier; CSF:
cerebrospinal fluid; CP: choroid plexus; ISF: interstitial fluid.
Author Contributions: Conceptualization, C.M. and E.C.; investigation, C.M, L.C., D.A. and E.C.;
resources, C.M, L.C., D.A. and E.C.; writing—original draft preparation, C.M. and E.C.; writing—
review and editing, C.M. and E.C.; funding acquisition, E.C. All authors have read and agreed to the
published version of the manuscript.
Funding: This study was supported by grants from CIBERNED (CB07/502, PI2021/03) and Funda-
cion Española para la Investigación en Parkinson (2020/0123).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data is contained within the article.
Conflicts of Interest: The authors declare no conflict of interest.
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