The choroid plexus is a tissue located in the lateral ventricles of the brain and is composed mainly of choroid plexus epithelium (CPE) cells.
CPE consists of a single layer of cuboidal epithelial cells that reside on a basement membrane.
Beneath the basement membrane is a network of fenestrated capillaries that are surrounded by connective tissue composed of fibroblasts and immune cells.
By virtue of the tight junctions between them. a blood–CSF barrier is formed.
The main function is currently thought to be the secretion of cerebrospinal fluid and the regulation of its pH.
The choroid plexus assists in the removal of metabolic waste and participates in the apoptotic pathway.
Its helps to repair the brain by regulating the secretion of neuropeptides and the delivery of drugs, and is involved in the immune response to assist in the clearance central nervous system infections.
The CPE is a very efficient secretory epithelial tissue in the body, secreting CSF at a rate of up to 0.4 ml/minute per gram of tissue.
The amount of CSF in the entire ventricular system of the human brain is estimated to be about 150 ml, but the CPE produces 500 to 600 ml of CSF every 24 h.
The presence of an inflammatory state damaging the brain causes changes in the choroid plexus cilia and results in an abnormal physiological state which leads to fluid alterations and triggers hydrocephalus.
Do to multiple factors, cerebrospinal fluid (CSF) circulation becomes impaired and CSF accumulates excessively causing enlargement of the ventricular system, damaging the cerebral vasculature and injuring the neurological function of the patient.
In Alzheimer’s disease, altered expression of type I and II interferons occurs and recruits immune cells to the central nervous system, increases β-amyloid (Aβ) in the CP, leading to damage of capillary and interstitial fibrosis.
Aβ causes increased expression of pro-inflammatory cytokines and matrix metalloproteinases, which in turn leads to downregulation of tight junction proteins, resulting in disruption of the blood–CSF barrier, making it impossible to clear Aβ.
Inflammatory diseases such as meningitis, and the inflammatory response of the body to fight the infection also stimulates the secretion of CSF from the choroid plexus epithelium, causing the accumulation of CSF.
In the brain there is a system for removal of intracranial material similar to the lymphatic system, and named it the glymphatic system.
CSF is produced by the epithelium of the CP, travels through a certain pathway, and is finally absorbed by the venous sinuses. Injury to any part of this process can lead to abnormal CSF levels and result in hydrocephalus.
In the glymphatic system , CSF from the subarachnoid space is driven into the perivascular spaces of the arteries on the surface of the brain, and flows into the brain parenchyma via aquaporin (AQP) on astrocytes, resulting in interstitial fluid (ISF).
The interstitial fluid which in turn flows into the perivascular spaces of the veins,and can be eliminated by blood circulation.
When the removal of substances from the glymphatic system is reduced, it leads to hydrocephalus.
CSF secreted by the choroid plexus epithelium (CPE) flows along a specific pathway and is absorbed by the venous sinuses.
An imbalance between the production of CSF by the CPE and its absorption by the venous sinuses, can lead to hydrocephalus in any part of the circulatory flow.
Brain parenchyma is permeable to water through water channel proteins and ion channels.
Another cause of hydrocephalus may also be due to the accumulation of hyperosmotic substances and impaired transport of substances in the CSF.
With a higher osmotic pressure of the CSF within the ventricles, the more water collects in the ventricles, which in turn forms hydrocephalus.
Targeting choroid plexus epithelium as a novel therapeutic strategy for hydrocephalus
Recent studies estimate that approximately 80% of the CSF is secreted by the CPE, with the remaining 20% coming from the brain interstitial fluid.
CSF is replaced three to four times per day.
With the rapid secretion of CSF, if there is an associated blockage in the circulatory pathway, it can result in a
ventricular dilation and even increased intracranial pressure, eventually leading to hydrocephalus (obstructive hydrocephalus).
Communicating hydrocephalus, on the other hand, is relatively uncommon due to an obstruction of CSF circulation, but rather an obstruction of CSF absorption.
Either intrinsic genetic factors or external environmental factors
that substantially promote the secretion of CSF from the choroid plexus or disrupt the reabsorption of CSF.
This leads to the accumulation of CSF in the ventricles and the development of hydrocephalus.
It is suspected that changes in osmotic pressure between CPE and capillaries can also lead to abnormal accumulation of CSF, which in turn leads to hydrocephalus.
This is the relationship between the choroid plexus and hydrocephalus, and the theory behind choroid plexus cautery.
There are four CPE located in the bilateral lateral ventricles, the third ventricle and the fourth ventricle: form the main component of brain-CSF fluid barrier (BCSFB).
The cells that make up the CPE are single layer cuboidal and low cylindrical epithelial cells located in the basement membrane.
These cells contain a large number of mitochondria, a central nucleus, abundant Golgi apparatus, and vesicles that increase in size toward the surface of the lumen.
There are a large number of distributed microvilli results in a substantial increase in the surface area of the luminal membrane.
In addition to microvilli, CPE cells must contain a small tufts of motile cilia.
Connections between CPE cells include tight junctions, intermediate junctions, and desmosomes, allowing large amounts of fluid movement.
The choroid plexus epithelium transports water and ions, which are the major components of cerebrospinal fluid, and regulates its pH.
These transport processes require the transport proteins, such as aquaporin, which is involved in water transportation, and Na+-K+-ATPase, which is involved in the transport of various ions of mainly Na+ and K+.
The choroid plexus epithelium removes metabolic wastes.
CPE is involved in the secretion and regulation of some neuropeptides,
serves as a transport channel for the delivery of certain drugs to the central nervous system, and is involved in the apoptosis pathways of other cells.
During an inflammatory response, the connections between cells in the CPE change, allowing some immune cells to pass through and participate in the response.
The CPE is polarized in a similar way to other epithelia, with a basal membrane, separated from the luminal membrane by means of tight junctions, which are lined with microvilli and motile cilia.
CPE express proteins such as Na+-K+-ATPase, sodium potassium chloride co-transporter 1 in the luminal membrane.
Such proteins are incorporated into specific amino acid sequences during endoplasmic reticulum synthesis, which in turn are recognized by the rough endoplasmic reticulum–Golgi complex axis, which determines the classification of proteins for targeted transport vesicles in the trans-Golgi complex network.
The CPE is composed of a single layer of cuboidal epithelial cells.
The function of these cells is to produce CSF.
Secretion of CSF, is mediated by a variety of membrane proteins that allow water and solutes to be transported across the epithelium, across the BCSFB, and from the blood side to the CSF side.
Water transport in the CPE is coupled with solute transport, resulting in near-isotonic transport.
Water transport in the CPE is associated with AQP, a transmembrane water transport protein.
AQP1, AQP3, AQP4, AQP5, AQP8, and AQP9 are currently identified in the brain.
AQP1 being the most critical and playing an important role in the overall process of water transport.
AQP1 and AQP5 are key water channel proteins that control water flux within the CP barrier and the production of CSF In mature tissues.
AQP1 is mostly expressed apically in the epithelium, indicating solutes diffusion from the CPE to the ventricles.
Differential changes in AQP1 expression may be associated with different types of hydrocephalus.
After intraventricular hemorrhage (IVH) combined with post-hemorrhagic ventricular dilatation (PHVD), AQP1 expression rises first as an early adaptive mechanism to increase intracerebroventricular water content and decrease CSF osmolarity.
AQP1 decreases later, belonging to autocrine regulation, decreasing water permeability in the CP and decreasing CSF production.
The expression of AQP5 rises, contributing to the protection of the extracellular matrix and the strength of tight junctions, thereby strengthening the function BCSFB.
In obstructive hydrocephalus and subarachnoid hemorrhage (SAH), the expression of both AQP1 and AQP4 rises, speeding up water transport, allowing an increase in the water content of the CSF, thus decreasing the osmotic pressure
In communicating hydrocephalus, AQP1 expression is also elevated.
Na+ is the most important ion that powers the secretion of CSF.
The transporter proteinNa+–K+-ATPase, transports Na+ into the CSF, and forms electrochemical gradients to help other ion transporters.
Additional transporters are epithelial Na+ channel (ENaC), NKCC1, electrogenic co-transporter NBCe2, and Na+–borate cotransporter.
The mechanism of K+ transport by the CP is very complex.
and relies on transport proteins in addition to K+ channels in the luminal membrane recirculate K+, which creates a negative membrane potential and thus maintains a certain electrochemical gradient in the CPE.
Ca2+ plays many important roles within the central nervous system, regulating many physiological processes and is a key factor in maintaining the stability of various signaling pathways,and
5-HT2c receptor agonists can promote spontaneous calcium activity
Some drugs inhibit the production of CSF by inhibiting the excretion of Cl−.
Arginine pressor (AVP) activates receptor V1, which inhibits the ability of the CPE to transport Cl−, thereby reducing CSF formation.
CPE has been shown to be involved in the transport of albumin and some amino acids.
The CPE is able to transport water, ions and other substances across the cells, across the BCSFB and into the CSF from the blood, thus serving to secrete CSF.
Most of the drugs currently used to treat hydrocephalus work by inhibiting the production of cerebrospinal fluid by inhibiting these transport proteins or their related enzymes.
With increasing age β-amyloid (Aβ) clearance-related proteins in CPE tissues decreases and the clearance capacity decreases, causing the accumulation of Aβ.
Impaired clearance of metabolic products, may cause changes in the osmotic pressure of the CSF, which in turn may lead to accumulation of CSF and cause hydrocephalus.
Leukocytosis in the CSF suggests that the CP, located at the junction of blood and CSF, is a multifunctional organ that serves as a gateway for immune cells to enter the CSF.
The CP plays an important role in immune surveillance and regulation of immune cell transport.
The CPE cell surface expresses adhesion molecules and presents antigens to T cells that supports immune cell trafficking and immune surveillance.
Epithelial cells release chemokines in a that attract immune cells to the surface and promote migration, suggesting that epithelial cells are a key factor in immune cell transit
The CP as a niche for T cell stimulation, contains CD4+ effector memory cells that retain a TCR (T cell receptor) profile against CNS antigens.
T cell-mediated immunity affects the CP and attenuates the secretion of IL-4 (interleukin 4), which is associated with brain aging and may serve as a therapeutic target for reversing or halting age-related diseases such as dementia.
CPE cells are involved in pH regulation of the CSF, and regulates the neuropeptides to help recover from damage to the brain.
In the CSF secreted by CPE, neuropeptides are regulated by an endocrine-like mechanisms that uses the flow of CSF to aggregate neuropeptides, including:brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), fibroblast growth factor (FGF), glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor (IGF), nerve growth factor (NGF), pituitary adenylate cyclase activating polypeptide (PACAP) and vascular endothelial growth factor (VEGF).
These neuropeptides are transported to the damaged part to help repair the brain damage caused by traumatic brain injury.
The BCSFB which is one of the major barriers of the CNS that allows the exclusion of pathogens capable of causing disease.
The CPE is a highly vascularized tissue that provides an important interface between the blood and the CNS.
There are pathogenic agents that can break through the physical barriers, biochemical barriers and immune barriers by various means, which turns the CPE into a portal of entry for pathogens into the CNS.
Pathogens interact with host cells and stimulate specific cellular signals, cell surface Toll-like receptors (TLR family) activate transcription factors (TF), commonly NF-κB.
These interactions regulate cell death, both apoptosis and necrosis.
Pathogens also regulate the gene expression profile of the host cell, both up- and down-regulated, as evidenced by altered secretion profiles of some proteins.
There are surface protein receptors and matrix metalloproteinases involved in the inflammatory response, as well as cytokines and chemokines that attract immune cells to clear pathogens.
The p75 neurotrophin receptor is expressed in the CP and is localized to the luminal membrane of epithelial cells., and has dual function: promoting survival and inducing apoptotic signaling througwhich in turn alters antibody clearance and inhibits neuronal growth by inducing apoptosis through p75NTR.
The CP blood–CSF barrier interface, is an epithelium that can be used to sparingly deliver drugs to the brain.
Drugs delivered from the blood to the lateral ventricles are delivered through the CSF to the ventricles and are used to regulate secretion and help treat disease.
CP delivers neurotrophic and growth factors to neurons by means of the CSF network.
There are a large number of microvilli distributed in the luminal membrane, providing a large surface area for molecular fluxes, and a large number of mitochondria provide energy for secretion and reabsorption.
Receptors for AVP (arginine vasopressin) and ANP (atrial natriuretic peptide) in CP are targets for agents to reduce CSF formation, which can be used to treat hydrocephalus.
Cilia alteration due to gene deletion or hydraldehyde treatment
play an important role in the normal physiological regulation of the CPE.
Ciliary dysfunction leads to increased cAMP content and activation of PKA, which allows phosphorylation which in turn regulates related ion channels and ion transport proteins, resulting in increased secretion of Cl− and HCO3−, ultimately manifesting as increased CSF secretion, and promotes inflammatory response after injury.
Intraventricular hypertension causes the rupture of blood vessels, leading to a hemolytic phenomenon that releases extracellular hemoglobin (Hb) into the CSF and activates an inflammatory response.
Pro-inflammatory mediators that arise with traumatic brain injury (TBI) promotes the synthesis of the monocyte chemotactic substance CCL2, which is released into the CSF at the luminal membrane as well as at the basolateral membrane and promotes leukocyte crossing of the epithelial barrier.
The inflammatory response induces an increase in CSF secretion by the CPE to affect directly, or induces ciliary dysfunction to affect indirectly.
Obesity increases ainflammatory state, allowing increased cytokines in the CSF, leading to fibrotic changes that are arachnoid villi obstruction and reduced CSF uptake.
CSF circulatory dynamics are impaired.
With cilia deficiency and and impaired circulatory kinetics.
Ciliated CPE had higher trans-cellular activity, which may have increased CSF secretion along the trans-cellular secretory pathway of AQP1 street, or it may have increased trans-cellular transport of proteins, which increased CSF osmolarity and acted as a driving force to drive the AQP-mediated fluid transport
This suggests that any incomplete immaturity of CPE cells can affect CSF secretion and lead to hydrocephalus.
Impaired transport of water molecules and ions is the most important cause of abnormal CSF secretion, which will be described specifically below.
Based on the osmotic pressure theory
The accumulation of hypertonic substances in the CSF alters the osmotic pressure of the CSF and affects the transport of substances.
The main and most important cause is a series of transporter proteins for water molecules and ions, either missing or malfunctioning, or in the wrong place, which may cause abnormal secretion.
The functional transcription factor p73 regulates the production and reabsorption of CSF by regulating the water channel protein AQP3.
This leads to non-obstructive hydrocephalus.
When intracranial pressure increases the brain responds to the situation by reducing CSF, and the molecular mechanism behind this is the reduced ability of Cl− channels to release Cl−.
Higher level of estrogen increases the levels of cortisol and TNF-α, which in turn affects a number of transporter proteins, including the water channel protein AQP4, causing abnormal secretion of CSF.
The presence of large amounts of hypertonic substances in the CSF will produce a higher osmotic pressure that acts as a driving force to affect water transport.
In thrombin-derived hydrocephalus, part of the cause can be attributed to the degradation of the blood–CSF barrier by VE-cadherin through activation of signaling pathwaywhich increases its permeability and leads to leakage of CSF.
Toxic substances that are not removed from the CSF and accumulate in excess can damage the epithelial cells of the CP and are a possible cause of hydrocephalus, typically hemoglobin and free iron.
Lesions of choroid plexus that can lead to hydrocephalus:
Defective cilia- short, sparse or missing, can cause obstruction of cerebrospinal fluid flow
Disorder of transporters, both the decline of transport capacity and the decrease of protein quantity, will cause problems in cerebrospinal fluid secretion
Impaired ability of efflux transporters to remove metabolic waste will increase osmotic pressure and affect secretion, obstruction caused by inflammation is also the reason of obstruction of cerebrospinal fluid secretion
The increase of cytokines caused by obesity, Increase of cerebrospinal fluid osmotic pressure and absence of choroid plexus epithelial cells.
Treatment options:
Drugs are not effective in treating hydrocephalus, nor is there a surgical procedure that can ultimately solve the problem.
Treatment options focus on direct surgical destruction of the CP, drug or other means to inhibit the transporter protein, and cell transplantation being researched.
Surgical destruction of the CP, CP cautery using the electric knife has been used clinically.
Nearly 80% of the CSF is secreted by the choroid plexuses, with the remaining 20% coming from the interstitial fluid of the brain which is generated by the blood brain barrier.
The CPE has many types of transporter proteins: water channel protein AQP family is an important class of transporter proteins responsible for the transport of water molecules., and therefore studies using them as targets are widespread.
Upregulation of AQP has been found in several types of hydrocephalus or other related diseases, for example, upregulation of AQP1 and AQP4 in subarachnoid hemorrhage.
Na+–K+-ATPase is a transporter protein responsible for the transport of Na+ and K+ and plays a very important role in the secretion of CSF.
Atrial naturetic protein binds to the CPE, producing cAMP, inhibiting the sodium pump and reducing sodium uptake, leading to altered ion transport and slowed CSF production, and induces dark cell production, cell shrinkage, cytoplasmic condensation, and normal organelle appearance, possibly in an oassociated with a decrease in CSF.
Curcumin, the main component of turmeric rhizome, inhibits Na+–K+-ATPase and helps regulate CSF production.
The removal of substances accumulated in the ventricles, such as hemoglobin and its degradation products, platelets, and leukocytes, reduces osmotic pressure, attenuates damage to CPE cells, and decreases CSF secretion.
The upregulation of efflux molecular transport proteins also removes substances accumulated within the ventricles and relieves hydrocephalus.
Presently, clinical treatment of hydrocephalus uses some dehydrating drugs to reduce edema, and surgery of shunt surgery and ventriculostomy (such as endoscopic third ventriculostomy).