Aquaporin-4 as the Main Element of the Glymphatic System for

Clearance of Abnormal Proteins and Prevention of Neurodegeneration:

A Review

IGOR SHIROLAPOV1,2, ALEXANDER ZAKHAROV1, 3, SAIKAT GOCHHAIT1,4,

VASILIY PYATIN1, 2, MARIYA SERGEEVA1,2, NATALIA ROMANCHUK1,2,

YULIYA KOMAROVA1, VLADIMIR KALININ3, OLGA PAVLOVA2, ELENA KHIVINTSEVA3

1Research Institute of Neurosciences,

Samara State Medical University,

RUSSIA

2Department of Physiology,

Samara State Medical University,

RUSSIA

3Department of Neurology,

Samara State Medical University,

RUSSIA

4Symbiosis International (Deemed University),

INDIA

Abstract: - Background: In the last decade, the concept of the Glymphatic system as a complexly organized

perivascular transport has been formed, it “connects” the cerebrospinal fluid with the lymphatic vessels of the

meninges through the extracellular space of the brain. The exact molecular mechanisms of the functioning of the

glymphatic pathway have not been fully characterized, but its key role in the cerebral clearance of metabolites

and neurotoxic substances is noted. Neurodegenerative diseases affect millions of people around the world, and

the most common pathologies from this heterogeneous group of diseases are Alzheimer's disease and

Parkinson's disease. Their pathogenesis is based on abnormal protein aggregation, formation of neurofibrillary

insoluble structures, and inefficient removal of neurotoxic metabolites. Aim: This article reviewed the evidence

linking glymphatic system dysfunction and the development of human neurodegenerative diseases, and noted

the key role of aquaporin-4 in the clearance of metabolites from the brain. Setting and Design: The actual

sources of data were compiled and reviewed from PubMed, Scopus, and Web of Sciences from 2012 to 2023.

Result and Discussion: Glial-dependent perivascular transport promotes the clearance of interstitial solutes,

including beta-amyloid, synuclein, and tau protein, from the parenchymal extracellular space of the brain in

normal and pathological conditions. An increase in the proportion of metabolites and pathological proteins in

the dysfunction of the glymphatic pathway enhances the progression of cognitive impairment and

neurodegenerative processes. In turn, the aging process, oxidative stress, and neuroinflammation in Alzheimer's

disease and Parkinson's disease contribute to reactive astrogliosis and may impair glymphatic clearance.

Conclusion: This review describes in detail the features of the glymphatic system and discusses that its

dysfunction plays a fundamental significance in the pathological accumulation of metabolites during the

progression of neurodegeneration and neuroinflammation. Understanding these processes will make it possible

to take new steps in the prevention and treatment of neurodegenerative diseases.

Key-Words: - glymphatic system, neurodegenerative diseases, amyloid, tau protein, aquaporin-4, astrocytes.

Received: May 21, 2022. Revised: August 24, 2023. Accepted: September 19, 2023. Published: October 9, 2023.

1 Introduction

Imbalances in homeostatic functions that maintain

fluid exchange and solutes included in the brain

tissue, which can be observed both in normal

conditions and in the development of

neuropathology, have long-term consequences from

impaired synaptic signaling to the onset of

neurodegenerative diseases (ND), [1]. Recent

studies of the glymphatic system form new insights

into metabolite clearance and natural sleep function

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DOI: 10.37394/23208.2023.20.11

Igor Shirolapov, Alexander Zakharov,

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during physiological aging and the pathogenesis of

ND. The glial-dependent pathway functions

predominantly during natural sleep and promotes

the excretion of neurotoxic substances in the CNS,

[2], [3], [4]. This highly organized cerebral

transport system includes perivascular spaces and

astrocyte cells, as well as aquaporin-4 (AQP4)

water channels. Studies have shown that the

glymphatic system is responsible for the clearance

of proteins responsible for the development of ND,

including Alzheimer's disease and Parkinson's

disease, and in experiments on mice, a significant

age-related decrease in glymphatic activity has been

noted, [5], [6], [8], [9]. These observations may

explain the increased vulnerability to

neurodegenerative processes and cognitive decline

in the elderly, as glymphatic pathway dysfunction

initiates further accumulation of neurotoxic proteins

and progression of ND, [10].

Failure of glymphatic transport has significant

and long-term consequences for humans, [11]. The

importance of the glymphatic system in cerebral

hydrodynamics, the features of its functioning

during brain aging, and possible disorders make it

relevant to study it in depth and many ways in

conjunction with the pathogenesis of

neurodegeneration characterized by abnormal

protein aggregation and insufficient removal of

neurotoxic metabolites.

2 Literature Review

Neurodegeneration and aging

Selective and progressive death of neurons is a

characteristic feature of neurodegeneration

processes and leads to certain neuronal

dysfunctions. Neurodegenerative diseases, the most

known of which are Alzheimer's disease and

Parkinson's disease, are responsible for a significant

proportion of cognitive and motor impairments in

the elderly. These pathologies affect more than 50

million people worldwide, with the vast majority of

cases being sporadic, [12]. ND is based on the

processes of abnormal aggregation of proteins such

as Aβ-amyloid, α-synuclein, tau protein, TDP-43,

and others, the formation of neurofibrillary

insoluble structures and their deposition in the form

of histopathological inclusions in the tissues of the

nervous system, [13] . It is noted that the frequency

of ND increases with age, which is considered the

most important non-modifiable risk factor for their

development. Determination of the level of Aβ42-

peptide is used as a biomarker of Alzheimer's

disease, with the progression of the disease, its

amount changes due to accumulation in the tissue.

Since extracellular amyloid-beta takes a certain

amount of time to be removed before it can be

incorporated into plaques, stable isotope tracers

have found that its turnover rate slows down with

age, [14], [15], [16].

The past study has analyzed more than a

thousand people aged 30-95 years and found an

increase in the risk of Alzheimer's disease with age,

especially in people over 70 years of age, [17].

Also, in cognitively healthy individuals, ligand

retention progressively increases with age in PET

examination with amyloids. The authors suggest

that the presence of at least one marker of cerebral

amyloidosis in the study of cerebrospinal fluid or

PET scans of cognitively normal individuals may

be sufficient to establish a diagnosis of an ND even

in the absence of any clinical manifestations, [18],

[19] . At the same time, determining the onset of the

disease is especially important for its prevention,

since it is impossible to establish what proportion of

healthy people with positive biomarkers will

progress to the clinical state of Alzheimer's disease.

A meta-analysis of the age-associated prevalence of

a positive beta-amyloid biomarker in three thousand

people with normal cognitive abilities revealed that

between the ages of 50 and 90 years, amyloid

pathology increased from 10% to 44%.

Simultaneously, a 20-30-year time interval was

noted between the first determination of a positive

amyloid biomarker and the onset of clinical

manifestations of dementia, [20] Even though great

progress has been made in understanding the

pathogenesis of neurodegeneration to date, initially

most of the research was focused on the study of

biomarkers and not on the analysis of principal

pathophysiological mechanisms, [21], [22], [23].

Glymphatic Pathway

With the accumulation of neurotoxic proteins in the

extracellular space, the immune effectors of the

CNS are activated, removing them and

simultaneously secreting pro-inflammatory

cytokines, [24], [25]. Amyloid-like proteins in

misfolded conformations and as neurotoxic

oligomers induce a reactive microglial response that

contributes to the subsequent degeneration of

synapses and neurons. Such proteins are highly

productive: for example, for β-amyloid, the

frequency is up to one molecule per second for each

neuron. Neurotoxic effects and microglial response

require highly efficient clearance mechanisms to

prevent their accumulation and progression of

neuroinflammation and neurodegeneration, [26].

The cleaning can occur through degradation by

enzymes or cellular uptake by neurons and glia.

There is strong evidence for clearance of Aβ and

tau protein into the cerebrospinal fluid, and the

blood-brain barrier is not the only CNS pathway for

these proteins, [27]. Animal studies have identified

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alternative clearance pathways in which solutes and

specific tracers that are not normally able to cross

the blood-brain barrier in large numbers are cleared

along the blood vessels into the meningeal

lymphatics, [28]. The so-called "glymphatic

pathway" is a glial-mediated highly organized fluid

transport system and can be considered the central

clearance system in the brain in both animals and

humans. The concept of the glymphatic system is

proposed based on scientific studies in which the

authors demonstrated predominantly convective

pathways for the movement of cerebrospinal fluid

and solutes using MRI neuroimaging. Dynamic

contrast-enhanced MRI has made it possible to

deeply study cerebral hydrodynamics in

experimental animals and has contributed to real-

time neuroimaging of perivascular inflow and fluid

exchange, [29], [30], [31], [32], [33]. After

intracisternal injection of a fluorescently labeled

tracer, the scientists observed a subarachnoid influx

of CSF into the periarterial spaces and further into

the brain parenchyma, where it mixed with the

interstitial fluid, followed by perivenous outflow. It

was shown that the rate of elimination of substances

was significantly higher than in the study of

diffusion processes, and the pulsation of cerebral

arteries is a key factor in perivascular exchange.

The cervical lymph nodes, which have a higher

level of amyloid compared to other regional lymph

nodes, are considered the primary gateway for the

entry of amyloid excreted from the brain

parenchyma into the systemic lymphatic

circulation, [34], [35]. Thus, the consideration of

certain mechanisms of cerebral transport of

substances contributed to the discovery that a

significant part of the liquor enters the brain tissue

by the perivascular route, and in the same way it is

removed.

The pathological relationship between the

development of neurodegenerative processes and

dysfunction of the glymphatic pathway is

confirmed in animal experiments, [36]. In mouse

models of neurodegeneration, a significant decrease

in interstitial solute clearance has been found

concomitant with an increase in β-amyloid levels.

These results have been observed in AQP4-

knockout rodents, suggesting that this cerebral fluid

transport is controlled by a specialized bidirectional

astrocyte water channel. In particular, dynamic

contrast-enhanced MRI showed a 55% reduction in

parenchymal clearance of Aβ protein, [28], [37],

[38]. These results support the hypothesis that a

significant fraction of soluble amyloid is excreted

by the perivascular route, as opposed to local

removal across the blood-brain barrier.

Aquaporin-4 and its key significance

The terminal feet of astrocytes are attached to the

wall of cerebral vessels; as a result, an exchange of

substances can occur between endotheliocytes and

the brain parenchyma. Glymphatic transport

facilitates the clearance of interstitial solutes,

including beta-amyloid and tau, from the

parenchymal extracellular space of the brain, [39],

[40]. Astrocytes release various bioactive

substances, neurotrophic factors, cytokines, and

express transport proteins and receptors, one of

which is the AQP4 water channel. A close

correlation between this protein and glymphatic

function was found in studies in AQP4 knockout

mice in which deletion of the water channel caused

impaired glymphatic clearance and intraneuronal

accumulation of amyloid proteins, [41], [42], [43].

Currently, the physiological mechanism of

AQP4-associated regulation of perivascular-

parenchymal transport continues to be studied.

Expression of aquaporin-4 on the plasma membrane

of astrocytes regulates cerebral water homeostasis,

and its pharmacological inhibition contributes to the

formation of edema, [43], [44]. This highly

selective water channel is maximally expressed at

the terminal perivascular sites of astrocytes, where

it covers a large percentage of the surface due to

association with DAC. The size of astrocyte

terminals varies along the vascular network,

correlating with the diameter of the vessels. In fluid

dynamics modeling, this change provides a nearly

constant flow through the glial spaces, [45]. Solutes

can pass from the periarterial spaces into the brain

parenchyma directly through the AQP4 and

astrocyte bodies or the gaps between the astrocytic

end feet. This process is modulated, and the

deletion of this water channel, and the defection of

its localization or polarization reduces glymphatic

flow, [46] . It is assumed that various biomolecules

can act as mediators and activators of glymphatic

transport, facilitating AQP4-dependent

hydrodynamics. In particular, studies using DCE-

MRI are investigating the significance of the TGN-

073, which has been shown to increase diffusional

water transport in the rat brain, [47] .

Impaired perivascular polarization of

aquaporin-4 correlates with a progressive decline in

the efficiency of glymphatic clearance in the aging

brain, [48]. In the mouse model of Alzheimer's

disease with extensive Aβ-amyloid deposits,

glymphatic transport of radioiodine-labeled protein

in older animals was reduced by 40% more than in

younger animals. Glymphatic clearance is reduced

to significant amyloid deposits in younger APP/PS1

mice expressing amyloid precursor protein and

mutant presenilin-1, compared to age-matched

controls, [49]. Soluble amyloid oligomers, as their

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more toxic form, are found predominantly not in the

cerebral parenchyma, but perivascularly near

AQP4-positive astrocytes. Moreover, compared

with young mice, the levels of soluble and insoluble

Aβ40 and Aβ42 were increased almost 2-fold, and

the number of soluble oligomers was increased 6-

fold in older mice .

A comparative analysis of the AQP4

cerebrospinal fluid level in patients with clinically

confirmed ND revealed an almost 2-fold increase

compared to healthy people, [4]. A positive

correlation of the level of tau protein was noted

with signaling proteins and molecules involved in

the processes of expression and fixation of

aquaporin-4 at the perivascular ends of astrocytes,

which additionally links the role of this water

channel with the pathogenesis of proteinopathic

diseases. In mouse models, deletion of aquaporin-4

significantly increased levels of tau in the

cerebrospinal fluid of transgenic mice expressing

mutant tau and promoted increased deposition of its

phosphorylated form, exacerbating subsequent

neuronal degeneration, [50], [51] . Genetic studies

of single nucleotide polymorphisms showed a

functional relationship between the genetic

variability of the AQP4 channel and its efficiency,

impact on accumulation and clearance of amyloid,

cognitive decline, progression of the ND and its

outcome, [52], [53], [54].

Since oligomers and neurofibrillary lesions

stimulate the release of pro-inflammatory cytokines

with the participation of microglia, inflammation is

an important link in the pathogenesis of the

neurodegenerative process. In experiments on

knockout mice, the microglial response increases

phagocytosis of Aβ-amyloid in the cerebral cortex.

At the same time, the selective elimination of

microglia in the frontal cortex of mice leads to the

deposition of Aβ protein. Simultaneously,

suppression of the expression of Apolipoprotein E

reduces intraneuronal amyloid levels in a mouse

model of neurodegeneration and the deletion of

aquaporin-4 in such mice, [55].

Pharmacological enhancement or long-term

stimulation of slow-wave sleep in animal models of

Parkinson's disease and Alzheimer's disease

promotes glymphatic transport, perivascular

expression of AQP4, and reduces the accumulation

of α-synuclein and β-amyloid. A potential

relationship between the activity of the glymphatic

system and the quality of sleep, dysfunction of

clock genes, and dysregulation of circadian rhythms

in ND was noted, [56], [57], [58]. The correlation

between proteinopathies and disorders in the sleep-

wake cycle confirms the fundamental role of

normal natural sleep in the elimination of

neurotoxic substances. It has been established that

glymphatic activity is significantly increased during

natural sleep: perivascular CSF inflow and

interstitial solute outflow occur faster during sleep

compared to the waking brain, [59]. At the same

time, age-related disturbances in the regulation of

the sleep-wake cycle, and changes in the

architecture and depth of sleep not only correlate

with a decrease in cognitive functions in the elderly

but also contribute to impaired glymphatic

clearance of metabolites, the accumulation of

amyloidogenic proteins and the progression of

neurodegenerative processes in humans and animal

experiments, [60], [61], [62], discovered

perivascular aggregation of α-synuclein and

abnormal polarization of AQP4 in a mouse model

of Parkinson's disease. In combination with

glymphatic dysfunction, neurodegeneration, and α-

synuclein aggregation were further enhanced by

cervical lymph node ligation, [62]. Thus,

glymphatic turnover is a physiologically regulated

process in which perivascular CSF inflow and

clearance occur faster during sleep and are altered

by circadian dynamics, [63], [64] .

3 Conclusion

Disturbance of cerebral hydrodynamics and

glymphatic clearance is involved in the

pathogenesis of a number of brain diseases, in

particular neurodegenerative and demyelinating

diseases, and sleep disorders. Changes in the

glymphatic system and aquaporin-4 expression as

its main determinant are reported in hydrocephalus,

stroke, traumatic brain injury, cerebral amyloid

angiopathy, multiple sclerosis, diabetes mellitus,

and other pathologies, [65], [66], [67]. A decrease

in glymphatic activity and an increase in amyloid

levels can be considered as an early biomarker of

the onset of neurodegeneration, and the

development of methods and therapeutic

approaches to restore the normal clearance of

metabolites from the brain can provide an

advantage in the prevention of normal aging and the

treatment of ND at the preclinical stage, [68] .

In recent years, the discovery and multifaceted

study of the glymphatic pathway has demonstrated

its importance in maintaining cerebral homeostasis.

Scientists have identified long-term consequences

of an imbalance in this system of perivascular

clearance, as well as significance in the progression

of neurological disorders (Figure 1). Since certain

neuropathology and age-related disorders occur

only in humans, we believe that it is necessary to

continue to look for new and offer alternative

methods, including in vitro, theoretical network,

and mathematical models that provide the

maximum level of control and personalization,

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taking into account the patient features, [69], [70],

[71]. In general, metabolite clearance dysregulation

associated with the assembly and accumulation of

pathological proteins can be fully extrapolated to

any experimental models of neurodegeneration,

since it is equally associated with impaired

glymphatic turnover, [72], [73].

Fig. 1: Schematic demonstration of the importance

of the glymphatic system in the pathogenesis of

neurological disorders

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Contribution of Individual Authors to the

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