The large numbers of transporters present at the blood—CSF barrier likely play crucial roles in energy metabolism, nutrient supply, as well as CSF production and neurotransmitter regulation in the brain, particularly during development. The now debunked dogma that the brain develops without functional brain barriers has been replaced with the realization that dysfunction of specific transporter mechanisms, either genetic or acquired through some pathological process, likely play more important roles in subsequent mal-development of the brain or neuropsychiatric disorder later in life than.
Thus these transporters are also potential pharmaceutical targets for treatment of such diseases, as they are possible targets for drug entry and toxin removal in both the developing and adult brain. CSF in the developing brain contains characteristically high concentrations of plasma-derived protein when compared to the adult.
The same trends are consistent for rodents, marsupials and humans. Although the route of this transfer has been identified as intracellular, the actual mechanism remains unknown Knott et al.
Once proteins have transferred across the choroid plexus into CSF, some are taken up into cells in the brain, while others continue through the ventricular system to be reabsorbed by the arachnoid granulations on the outer surface of the brain.
For example some neuroependymal cells lining the cerebral ventricles take up proteins such as albumin and the fetal protein fetuin Dziegielewska et al.
The initial cells that form the first layers of the neocortex in the embryo take up fetuin via apical dendrites in contact with the dorsal surface of the cortex Dziegielewska et al. Other plasma proteins such as albumin and alfa-fetoprotein are also transported via the same route from early during development, however, this uptake has been little studied and it is not clear whether the proteins themselves are functionally important or bound ligands such as hormones and growth factors are the precious cargo.
A recent publication indicated the number of plasma protein positive cells in the ventricular zone of a fetal mouse can be increased following an inflammatory response of the dam—indicating protein uptake by the brain can be physiologically responsive to alterations in uterine environment Stolp et al.
It is also known that this choroid plexus protein transport system is dynamic—able to adapt to acute alterations in levels of individual proteins circulating in the plasma Liddelow et al. What is not known is whether or not the choroid plexus is able to maintain the protein composition of the CSF after chronic alterations in circulating proteins.
The first cells that differentiate to become choroid plexus epithelial cells appear able to transport protein immediately, with no apparent preference provided to cells of different stages of development. Although there appears to be a higher degree of specificity for individual proteins earlier in the development Liddelow et al. The requirement for protein in the CSF and CNS is likely two-fold: initially the high protein concentration reported in the CSF of early developing animals sets up an osmotic pressure gradient causing the influx of water and consequently improving ventricular expansion and normal brain growth and development Johansson et al.
The choroid plexus is unique in the CNS in that the cells, once born and fully matured, do not undergo replacement or degeneration under normal conditions.
In the adult, the proliferation of choroid plexus epithelium has been shown to occur at a low rate—less than 0. There are few reports of disease of the choroid plexus epithelium itself many cases of plexus disability result from endothelioma of the blood vessels, invading metastatic cancerous growth accounting for less than 0.
It seems that regardless of case-study age, race, or location, these diseases of the choroid plexus are rare, and to date no study descriptions or animal models are able to accurately describe insufficiencies in normal plexus function although anencephalic expansion due to excess CSF production by the choroid plexuses is widely reported. Rarer still are descriptions of changes in the choroid plexus during normal aging. This fluid adequately nourishes the brain prior to full vascularization see above and provides buoyant suspension and protection to the brain and spinal cord.
During normal aging there have been reports of filamentous, ring-like or arc-like structures in the epithelium of the choroid plexus, termed Biondi bodies Biondi, ; Oksche and Kirschstein, ; Kiktenko, ; Wen et al.
Structurally these filamentous rings are associated with lipid droplets, and appear to develop within the epithelial cells themselves and thus may be agents of cellular destruction rather than in the extracellular matrix, however the study by Kiktenko makes special mention of the fact they were unable to find convincing signs of damage in plexus epithelial cells with large-sized Biondi bodies.
Inspection of the electron micrographs however clearly shows examples of these tangled rings bursting forth from ruptured plexus epithelial cells, while nearby ring-free cells are noticeably undamaged see Figure 4B. These Biondi bodies, or Biondi ring tangles, are not seen between adjacent cells - only in the cytoplasm of plexus epithelia.
This intracellular location of the Biondi bodies and their state of preservation compared to other cytoplasmic elements suggest a destructive effect on epithelial cells of choroid plexuses. The more common occurrence in Alzheimer's disease Miklossy et al. Choroid epithelial cells also acquire numerous other lipofuscin vacuoles along with Biondi bodies in Alzheimer's patients Miklossy et al. These Biondi inclusions have thus far proved difficult to image extensively, as the presence only in higher-order primates and humans presents issues for both tissue availability and preservation.
The light and transmission electron micrographs provided by Wen et al. Older material prepared for scanning electron microscopy by Kiktenko ; see Figure 4B was prepared from a wide range of aged and otherwise healthy human autopsies that were fixed within 1. In these images it is possible to see choroid plexus epithelial cells bursting, possibly due to Biondi ring inclusions and not an artifact of fixation as all burst cells contain these ring structures. Whatever their effect on the plexus, it is true to say that Biondi bodies are characteristic of choroidal epithelia of aged humans.
Their absence in young-to-middle aged non-human primates, as well as their absence in various senescent mammals rodents, dogs, and cats and birds, has led to suggestions they may relate to differences in brain senescence between humans and other animals. However, Biondi-like inclusions have been identified in an aged 43 year old male chimpanzee Oksche et al. Figure 4.
Biondi ring tangles in aged human choroid plexus of the lateral and fourth choroid plexus. A Fluorescent light micrograph of thioflavin S-stained Biondi ring tangles arrows in the choroid plexus of the brain of a year-old human female with Alzheimer's disease showing Biondi ring tangles appear as ring, tangle, serpentine, and curled profiles.
Arrow marks a ring bursting from an individual plexus epithelial cell. Material from 78 year old woman. C Electron micrograph of a choroid plexus from a year-old male with Alzheimer's disease showing the fibrous Biondi ring tangles one highlighted in pink, the other in green associated with lipofuscin granules, mitochondria, and other cellular components. A,C Reproduced from Wen et al.
All rights reserved. The choroid plexus therefore demonstrates a robust accumulation of pathological changes, in the form of Biondi bodies, with normal aging, however the changes to normal function are difficult to ascertain, as no rodent examples are reported thus study of their effects cannot be completed.
It is likely however these modifications could alter choroid plexus function, including synthesis, secretion, and transport of proteins and other molecules. A possible reason for this amazing cellular longevity is the high expression of the aging repressor Klotho Kl , see Liddelow et al. Mice deficient for KLOTHO protein manifest a syndrome similar to accelerated human aging and display rapid and extensive arteriosclerosis.
The high expression of Kl throughout plexus development and into the adult suggests some protective effect on plexus epithelial cells themselves, and also on other CNS cells— especially considering evidence that KLOTHO protein levels in the CSF are decreased in Alzheimer's disease humans Semba et al. To date, the only study of the choroid plexus in systemic disease has been reported by Dohrmann and Herdson Fine structural examination of the choroid plexus revealed an irregular, homogeneous thickening of the capillary basement membranes.
Other miscellaneous reports on the pathology of the choroid plexus include Hoff , Rand and Courville and Leviton et al. Hoff reported on increased permeability of the choroid plexus in experimental head injury. Another survey of 62 cases of fatal cerebral trauma noted oedema of the stroma and vacuolation of the epithelial cells of the choroid plexus Rand and Courville, The presence of amyloid in the choroid plexus of elderly brains was described by Divry in Blackwood et al.
Amyloid was present within the choroidal epithelium, confined to the free margins of the cells. As a structure that produces and secretes CSF, controls and protects the internal environment of the adult CNS, and is present even before vascularization of other cortical structures, surely we have sufficient evidence to justify serious investigations into this small epithelial tissue mass in the ventricles of all vertebrates.
This review has touched on the early development of the choroid plexuses, and its emergence as a possible location of serious complications in aging and disease. Indeed the close homeostatic control of the internal milieu of the CNS: the CSF, glia, and neurons, plays a vital role in normal and abnormal brain function. Dysfunctions of all of the brain barriers contribute heavily to the pathology of neurological conditions, however the added detriment of a dysfunctional choroid plexus during development is additional reason for concern.
A proper understanding of the choroid plexus will likely prove important for the production of drug delivery and therapies to help ameliorate a wide range of neurological diseases.
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Altman, J. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats.
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A possible transepithelial pathway via endoplasmic reticulum in foetal sheep choroid plexus. Monuki, E. However, there are specific transport systems that mediate transport of peptides.
The peptide transporters that belong to the peptide transporter PTR family are solute carrier proteins SLC15A responsible for the membrane transport of di- and tripeptides [ ]. Another peptide transporter family PTS , that contain at least 9 members PTS mediate transport of larger peptides more than 3 AAs in chain and in many tissues act primarily as an efflux pump, removing lipophilic peptides from cellular membranes.
PTRs couple substrate movement across the membranes to movement of protons down an inwardly-directed electrochemical proton gradient [ ]. Early studies have shown that arginine vasopressin AVP [ ], enkephalins [ , ], delta-sleep-inducing peptide DSIP [ ] and luteinizing-hormone-releasing hormone LHRH had a measurable volume of distribution in the guinea pig brain after in situ perfusion but the rates of blood-brain transfer were 10 3 4 fold lower than rates of carrier-mediated amino-acid transport.
Tetrapeptide tyrosine melanocyte-stimulating inhibitory factor 1 Tyr-MIF-1 was the first peptide shown to pass from blood to the brain by a saturable system [ ]. However, when PTS-6 expression in BECs was inhibited by antisense targeting, brain accumulation of PACAP increased significantly [ ], which indicates that the main role of this transporter is efflux transport. Thus, it appears that BBB transport system for peptides could be involved in impeding blood-to-brain ISF transfer of intact peptides.
The brain delivery of peptides is further impeded by the existence of various enzymes in BECs that modify AA side chains or hydrolyze peptide bonds. However, it has been shown that some neuropeptides, when present in capillaries, could be transferred to the brain ISF in intact form, like DSIP [ ]. Larger peptides and proteins that have receptors present at the luminal side of BECs could use receptor-mediated transcytosis to pass across the BBB and that mechanism was revealed for insulin [ ], transferrin [ ], certain cytokines [ ], leptin [ , ], immunoglobulin G [ ], and insulin-like growth factor [ ].
In adsorptive endocytosis, the interaction of a glycoprotein, or positively-charged peptide, with glycoproteins or negatively-charged regions of the BECs causes adsorption of the molecule to the surface of the BECs.
This in turn causes internalization of the molecule into the BEC [ ]. However, it is not clear what determines the fate of those vesicles; they could be delivered to the Golgi, or lysosomes, or they could move across the cytoplasm and fuse with the abluminal membrane [ ]. However, this strategy faces another obstacle, because with increasing lipid solubility sequestration by liver and binding to plasma proteins also increases, which decreases the half-life of a peptide in plasma and reduces availability for interaction with BECs.
For example, blood-to-brain transport of Tyr-MIF-1 and the enkephalins is very limited because of the action of PTS1 in the abluminal membrane of BECs, which mediates efflux of those peptides [ ].
Also, P-gp mediates efflux transport of several opiate peptides and inhibition of efflux pumps was accompanied by a several-fold increase in peptide accumulation by the brain [ ]. Another alternative strategy is to use receptor-mediated transcytosis through the BBB for drug delivery to the brain.
This strategy, known as a "Trojan horse", includes conjugation of different peptides that have very limited delivery to the brain to monoclonal antibodies against one of the BBB peptide receptors, like the transferrin receptor [ ]; binding of the antibody to receptor triggers endocytosis, as explained above.
However, these receptors are not brain specific and are widely expressed in peripheral organs, a fact that limits their applicability for brain-targeting. A recent study used phage display in an in situ brain perfusion model to screen for peptide ligands that bind specifically to brain endothelium [ ]. Using this strategy, new peptide ligands were identified that showed significant binding to human brain endothelium but not to other human endothelial cells, so they may be used for specific targeting of drugs to the blood-brain barrier [ ].
PEPT2 is a proton-coupled oligopeptide transporter and it is abundant in epithelial layers, including kidney, where it plays an important role in renal reabsorption of di- and tri-peptides [ , ].
Thus, the likely function of this transporter is to clear di- and tri-peptides from the CSF. An intense hybridization signal for PHT1 was found in the brain, especially in the hippocampus and cerebellum, while the signal in the CP was weaker [ ]. PEPTs also transport a number of peptidomimetics, so the presence of this transporter at the apical membrane of the CPE could severely restrict entry of blood-borne peptidomimetics into the CSF. The CPE is also involved in receptor-mediated endocytosis of peptides.
The CPs are important not only in clearance of peptides from the CSF and delivery of blood-borne peptides to the CSF, but also as a target for a number of hormones. Rats with congenital hydrocephalus had a lower number of binding sites for radiolabelled ANP in the choroid plexus, as compared to the control rats, indicating that this could be one of the pathophysiological mechanisms underlying excessive CSF production [ ].
The regulation of choroidal AVP synthesis is similar to that observed in the hypothalamus and it has been shown that chronic hypernatremia increases the expression of AVP in the CP [ ].
An important role of CP-born bioactive peptides is proposed in brain recovery after traumatic brain injury TBI. It is believed that upregulated growth factors and neurotrophins produced by the CPs and by the ependymal layer are brought by the CSF bulk flow to brain regions close to the ependymal layer and those factors could be important for neural restoration through enhanced neurogenesis and angiogenesis after TBI [ ].
An important feature of CPE, that is not present in the BECs, is a synthesis of transthyretin TTR , which functions as a carrier for thyroxin and retinol-binding protein [ ]. TTR, thyroxin-binding globulin TBG and albumin form a "buffering" system for plasma L-thyroxin because of their overlapping affinities for that hormone. However, absence of TTR in genetically-modified mice did not affect delivery of T4 to the brain [ ]. Also, expression of TTR both in vitro and in vivo was up-regulated by treatment with progesterone, which involves a progesterone receptor-mediated mechanism [ ].
These findings could at least partially explain mechanisms involved in protective effects of progesterone and estradiol against the onset of AD. Their substrates range from small ions to large polypeptides and transport occurs against steep concentration gradients using energy that is provided by ATP-hydrolysis [ ]. Transport of amphipathic molecules i. Members of the SLC21 family mediate transport of large, amphipathic solutes such as bile salts, thyroid hormones, leukotriene, and various steroids conjugates and xenobiotics [ ].
Substrates for OCTs include neurotransmitters 5-HT, dopamine , choline, tetraethylammonium ion, cimetidine, N1-methylnicotinamide [ ]. Given the mechanism of action of particular ABC transporters, the precise localization of these proteins at the BBB and BCSFB is essential for understanding their role in physiology and in drug delivery to the brain. For example, a luminally-located P-glycoprotein, which is quantitatively the most important ABC transporter at the BBB, would mediate efflux transport of its substrates from the luminal membrane back to blood, which would impede influx of substrates to the brain.
On the other hand, abluminally located P-gp would mediate transport of substrates from the abluminal membrane into the brain ISF, thereby facilitating influx of substrates to the brain. In brain capillaries, P-gp is predominantly and abundantly expressed in the luminal membrane [ ] and it mediates efflux of substrates back into the blood after they initially diffuse into the endothelial cell membrane Figure 4A. By this action, P-gp restricts penetration of its substrates into the brain.
A report has suggested that endothelial P-gp is expressed at the nuclear membrane of rat brain microvessel endothelial cell line RBE4 [ ]. In rodents, two multidrug resistance proteins are encoded by the genes Mdr1a and Mdr1b and only Mdr1a is found in endothelial cells [ ].
Studies using P-gp knockout mice have mainly contributed to the view of P-gp as the main gatekeeper at the BBB [ ]. The expression of MRPs is less clear and there are many conflicting reports: some authors suggested that BECs express multidrug resistance-associated protein Mrp1 for the review see [ ] at the luminal side, while others revealed by immunofluorescence staining that this protein is scarce at the BBB and localized abluminally [ ] Figure 4A.
In rodents, Oatp1a4 Slc21a5, old protein name Oatp2 , Oatp1a5 Slc21a7, old protein name Oatp3 and Oatp1c1 Slc21a14, old protein name Oatp14 are expressed at blood-brain interfaces with Oatp1a5 being located primarily abluminally and Oatp1a4 on luminal and abluminal membranes [ , , ].
Electrogenic organic cation transporters OCTs are expressed in rodent and human neurons and glial cells and not in BECs in humans [ ]. Some data indicate that in the BECs Mrp1 and P-gp may also be present in organelles and nuclear envelope. Membrane localization of Mrp1 in BECs is not completely clear, with some reports indicating that it is present at the luminal side, while others indicating that it is scarce and probably located at the abluminal side.
Mrp5 was detected in the CPE cells at the transcript level, but there are no functional or immunocytochemical data so far, indicating its cellular localization asterisk. The same stands for Oat2, Oct and Oatp9. Many of those transporters have also been identified in the CPs at the transcript or protein level or by functional transport studies [ ]. P-gp expression in the human and rodent CP has been detected [ , ], but other research groups have found P-gp in the CP to be scarce or undetectable [ , ].
Cellular localization of two Oatps in CP has been confirmed by immunochemical studies: Oatp1a4, Slc21a5, old protein name Oatp2 is located at the basolateral membrane, while Oatp1a5 Slc21a7, old protein name Oatp3 is located on the apical membrane [ , ], with Oatp2 being probably the most abundant Oapt in the CP [ ].
Oatp2b1 Slc21a9, old protein name Oatp9 and Oatp1c1 Slc21a14, old protein name Oatp14 were detected in CP at the transcript and protein level; precise cellular localization of Oatp9 is unknown [ ], while Oatp14 appears to be located primarily at the basolateral membrane Figure 4B , and is involved in thyroid hormone transport [ ].
Since P-gp appears to be the main gatekeeper at the BBB, a very important observation was that xenobiotics, environmental toxins and pollutants, mediators of inflammation and even the neurotransmitter glutamate could affect expression of P-gp in the BECs, thereby reducing or increasing drug delivery to the brain [ ].
A practical consequence of this mechanism is that treatment with drugs that are P-gp substrates could reduce delivery of other P-gp substrates to the brain.
Inflammatory signals have more complex effects on P-gp expression: initially they cause a loss in P-gp activity that is followed by delayed increase in activity and expression [ ]. The existing reports are conflicting: it has been revealed that brain capillaries of Alzheimer's patients have reduced expression of P-gp [ ] and increased expression of BCRP [ ]; however, a recent study by confocal microscopy that quantified peak fluorescence values of cross-sectional profiles of brain microvessels, revealed expression of P-gp protein to be significantly lower in hippocampal vessels of patients with AD compared to normal individuals, whereas that of MRP4 or BCRP protein was not changed [ ].
However, the same study reported that analysis of the sections at protein level via Western blotting or at transcript level by qPCR did not reveal significantly lower expression for either P-gp or BCRP [ ]. There is evidence suggesting that there is a bulk flow of the brain ISF from brain capillaries towards the ventricular space and that ISF merges with the CSF; this flow takes place predominantly along perivascular spaces for a review see [ ].
This indicates that there is a constant production of a "new" ISF in the brain which contributes to total volume of the CSF.
This process is essential for maintaining correct fluid balance in the brain. As in other tissues, the activity of this enzyme is tightly associated with cell volume regulation [ ]. In addition, rat brain endothelial cells express Kv1 and Kir2 potassium channels; these are probably located on both the luminal and abluminal sides of the BECs [ ] Figure 5A.
However, the CSF recovered from the brain, contains 2. It has been shown that following in vitro loading of BECs with small acid load, HCO 3 - influx was mainly responsible for the acid extrusion and it was mediated partially by Cl - dependent HCO 3 - transporters.
Ion transporters in the CPs have been studied intensively because ion transport across the CPE drives CSF secretion, which could be considered as the most apparent and the most important function of CPs. CSF has a number of important roles in brain homeostasis, including reduction of the effective weight of the brain by being submerged in CSF, removal of waste products of metabolism, removing excess neurotransmitters and debris from the surface lining epithelium and delivering signalling molecules for a review of CSF functions see [ ].
Bicarbonate transport by the CPE directly affects the pH of CSF, which in turn affects neuronal activity in the respiratory centre in the medulla oblongata.
Overall, two main processes are driven by ion transporters in the CP. First, the transepithelial basolateral-to-CSF movement of sodium, bicarbonate and chloride creates a small osmotic force driving net movement of water in the same direction.
Water movement across the CPE is via aquaporin 1, the waater channel which is abundantly expressed in the apical membrane and less so in the basolateral membrane Figure 5B. This water channel is typical for epithelia that have a high rate of water transfer generated by a small osmotic gradient.
Second, CSF to basolateral movement of potassium takes place [ , ]. Two major anions, Cl - and HCO 3 - also pass the CPE layer via a transcellular route; the CSF concentrations of both Cl - and HCO 3 - are less than predicted for simple diffusion, which suggests that the paracellular route contributes negligibly to the overall transfer. Mice that had this transporter genetically removed had severe reduction in brain ventricle size, which suggested that the rate of CSF secretion was decreased [ ].
Transport of these ions through the apical membrane to the CSF involves several proteins. This channel Clir plays some role in apical HCO 3 - extrusion in mammals, but permeability of this channel for HCO 3 - appears to be small. Studies of the past two decades have provided insight into the molecular biology which underlines function of the two most important blood-brain fluid interfaces, the BBB and the BCSFB.
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