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Distribution of sodium transporters and aquaporin-1 in the human choroid plexus.

The choroid plexus epithelium secretes electrolytes and fluid in the brain ventricular lumen at high rates. Several channels and ion carriers have been identified as likely mediators of this transport in rodent choroid plexus. This study aimed to map several of these proteins to the human choroid plexus. Immunoperoxidase-histochemistry was employed to determine the cellular and subcellular localization of the proteins. The water channel, aquaporin (AQP) 1, was predominantly situated in the apical plasma membrane domain, although distinct basolateral and endothelial immunoreactivity was also observed. The Na(+)-K(+)-ATPase alpha(1)-subunit was exclusively localized apically in the human choroid plexus epithelial cells. Immunoreactivity for the Na(+)-K(+)-2Cl(-) cotransporter, NKCC1, was likewise confined to the apical plasma membrane domain of the epithelium. The Cl(-)/HCO(3)(-) exchanger, AE2, was localized basolaterally, as was the Na(+)-dependent Cl(-)/HCO(3)(-) exchanger, NCBE, and the electroneutral Na(+)-HCO(3)(-) cotransporter, NBCn1. No immunoreactivity was found toward the Na(+)-dependent acid/base transporters NHE1 or NBCe2. Hence, the human choroid plexus epithelium displays an almost identical distribution pattern of water channels and Na(+) transporters as the rat and mouse choroid plexus. This general cross species pattern suggests central roles for these transporters in choroid plexus functions such as cerebrospinal fluid production.

Amino Acid Sequence↗

Effect of serotonin on blood flow to the choroid plexus.

The choroid plexus contains a very high density of serotonin receptors and serotonin has been reported to influence the rate of formation of cerebrospinal fluid. The goal of this study was to examine effects of serotonin (5-hydroxytryptamine) on blood flow to the choroid plexus. Blood flow to the choroid plexus was measured in anesthetized cynomolgus monkeys and dogs using radioactive microspheres. Under control conditions, blood flow to choroid plexus was approximately 4 times greater than blood flow to the cerebrum in monkeys and approximately 7 times greater than blood flow to the cerebrum in dogs. Infusion of serotonin (40 micrograms.kg-1.min-1) into the left atrium increased blood flow to choroid plexus by 101 +/- 26% (mean +/- S.E.M.) in monkeys and by 201 +/- 45% in dogs. Serotonin did not affect cerebral blood flow. These findings suggest that serotonin may play an important role in regulation of blood flow to the choroid plexus.

Animals↗

Chronic lead exposure alters transthyretin concentration in rat cerebrospinal fluid: the role of the choroid plexus.

The choroid plexus, which is responsible for the maintenance of the biochemical milieu of the cerebrospinal fluid (CSF), avidly sequesters Pb. In order to test the hypothesis that chronic Pb exposure may impair choroid plexus function, male weanling Sprague-Dawley rats were exposed to Pb in drinking water at doses of 0, 50, or 250 micrograms Pb/ml (as Pb acetate) for 30, 60, or 90 days. The function of the choroid plexus was assessed as reflected by CSF concentrations of transthyretin (TTR, a major CSF protein manufactured by brain choroid plexus) and CSF essential metal ions (Ca2+, Mg2+, K+, and Na+). TTR concentrations were determined by radioimmunoassay using a monospecific rabbit anti-rat TTR polyclonal antibody, and CSF metal ions analyzed by flame atomic absorption spectrophotometry. Two-way ANOVA of CSF TTR concentrations revealed highly significant dose (p < 0.0001), time (p < 0.0223), and dose-by-time effects (p < 0.0379). Moreover, the percentage of reduction of CSF TTR was directly correlated with Pb concentrations in the choroid plexus (r = 0.703, p < 0.05). Pb exposure significantly increased CSF concentrations of Mg2+, but did not markedly altered CSF concentrations of Ca2+, K+, and Na+. Histopathologic examination under the light microscope did not show distinct alterations of plexus structure in Pb-treated rats. Since TTR is responsible for transport of thyroid hormones to the developing brain, we postulate that the depression of choroid plexus TTR production (and/or secretion) by Pb may impair brain development in young animals by depriving the CNS of thyroid hormones.

Administration, Oral↗

An experimental and ultrastructural study on the development of the avian choroid plexus.

The choroid plexus consists of the choroidal epithelium, a derivative of the neural tube, and the choroidal stroma, which originates from the embryonic head mesenchyme. This study deals with epithelio-mesenchymal interactions of these two components leading to the formation of the organ. Grafting experiments of the prospective components have been performed using the quail-chicken marker technique. Prospective choroidal epithelium of quail embryos, forced to interact with mesenchyme of the body wall of chicken embryos, gives rise to a choroid plexus showing normal morphogenesis and differentiation. The choroidal epithelium induces the differentiation of organ-typical fenestrated capillaries, which are highly permeable to intravenously injected horseradish peroxidase. The choroidal epithelium of the grafts constitutes a blood-cerebrospinal fluid barrier. On top of the choroidal epithelium, there are epiplexus cells displaying a typical ultrastructure. The experimental results show that these cells do not originate from the transplanted neural epithelium. Prospective choroidal stroma of chicken embryos does not exert a choroid plexus-inducing influence upon a quail embryo's neural epithelium isolated from parts of the brain that normally do not develop a choroid plexus. The experiments show that the choroidal epithelial cells are determined at least three days before the first organ anlage is detectable.

Animals↗

Prolactin enhancement of its own uptake at the choroid plexus.

The choroid plexus contains PRL receptors that function in part to transport PRL from the blood into the cerebrospinal fluid (CSF). The blood PRL concentration of female rats was altered by 1) three daily injections of haloperidol (chronic hyperprolactinemia) with or without bromocriptine administration 4 h before death, 2) bromocriptine alone for 4 h (acute hypoprolactinemia), and 3) a single vascular injection of ovine PRL (acute hyperprolactinemia). Changes in the uptake of PRL by the choroid plexus was assessed by quantitative in vivo autoradiography after the injection of radiolabeled PRL. Correlation of changes in PRL uptake at the choroid plexus with changes in PRL transport from blood to CSF was evaluated by subjecting CSF samples to sodium dodecyl sulfate-polyacrylamide gel electrophoresis after vascular injection of radiolabeled PRL. Autoradiography revealed that both chronic and acute hyperprolactinemia resulted in a significant increase in the uptake of radiolabeled PRL by the choroid plexus compared to that in untreated control animals. In contrast, bromocriptine had no effect on PRL uptake at the choroid plexus relative to that in control (untreated) animals. Chronic hyperprolactinemia, but not acute hyperprolactinemia, resulted in a significant increase in the transport of radiolabeled PRL from the blood to the CSF compared to that in untreated controls. The results are consistent with the up-regulation of PRL receptors in the choroid plexus by circulating PRL and the consequent augmentation of transport of PRL from blood to CSF.

Animals↗

Serotonin agonists increase transferrin levels via activation of 5-HT1C receptors in choroid plexus epithelium.

Choroid plexus epithelial cells are enriched in mRNA for proteins such as the iron carrier transferrin, which acts as a trophic factor in the brain. Choroid plexus epithelial cells also have a high density of 5-HT1C receptors linked to activation of the phosphoinositide (PI) hydrolysis second messenger system. The present studies show that the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potently increases PI hydrolysis and the levels of transferrin in primary cultures of rat choroid plexus epithelial cells. These effects are blocked by the 5-HT1C/5-HT2 receptor antagonists mesulergine and mianserin, but not by the 5-HT2 receptor-selective antagonist spiperone. Similarly, mesulergine and mianserin, but not spiperone, block the increases in transferrin levels and PI hydrolysis elicited by 5-carboxamidotryptamine (5-CT), a 5-HT1 receptor-selective agonist, and by serotonin. We conclude, therefore, that 5-HT1C receptor activation in the choroid plexus leads to an increase in the production of transferrin. By promoting transferrin synthesis in the choroid plexus, 5-HT may indirectly influence brain development and differentiation.

Amino Acid Isomerases↗

Malignant evolution of choroid plexus papilloma.

Choroid plexus tumors are rare CNS neoplasms. The distinction between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC) is made on the basis of clinical and histological criteria. Malignant evolution of CPP may occur, and the presence of mitotic figures in CPP may predict the likelihood of recurrence or malignant evolution. Close surveillance is mandated for these patients. We report on two such cases of CPP that transformed to CPC at the time of recurrence.

Cell Transformation, Neoplastic↗

No evidence of hSNF5/INI1 point mutations in choroid plexus papilloma.

Choroid plexus carcinomas (CPC) have been shown to carry mutations in the hSNF5/INI1 gene on chromosomal arm 22q11.2. A recent study on choroid plexus papillomas (CPP) and CPC revealed frequent losses of chromosomal portions on the long arm of chromosome 22 (-22q). The region harbouring hSNF5/INI1 was affected in 47% of the CPP and 73% of the CPC, respectively. -22q occurred more frequently in adult than in infantile CPP suggesting different pathogenetic pathways for these tumours. These findings may indicate a potential tumour suppressor gene function of hSNF5/INI1 in a subset of choroid plexus tumours. In order to examine its potential role in the pathogenesis of choroid plexus tumours, we analysed exons 1-9 of hSNF5/INI1 by SSCP analysis in a series of 21 formalin-fixed and paraffin-embedded CPP. No alterations in migratory patterns were detected. These data indicate that somatic point mutations of hSNF5/INI1 do not play a role in the pathogenesis of CPP and that CPP and CPC may arise by two different molecular pathways.

Choroid Plexus Neoplasms↗

Choroid plexus tumours.

Choroid plexus tumours are rare epithelial brain tumours and limited information is available regarding their biology and the best treatment. A meta-analysis was done to determine prognostic factors and the influence of various treatment modalities. A thorough review of the medical literature (1966-1998) revealed 566 well-documented choroid plexus tumours. These were entered into a database, which was analysed to determine prognostic factors and treatment modalities. Most patients with a supratentorial tumour were children, while the most common sites in adults were the fourth ventricle and the cerebellar pontine angle. Cerebellar pontine angle tumours were more frequently benign. Histology was the most important prognostic factor, as one, five, and 10-year projected survival rates were 90, 81, and 77% in choroid plexus-papilloma (n=353) compared to only 71, 41, and 35% in choroid plexus-carcinoma respectively (P<0.0005). Surgery was prognostically relevant for both choroid plexus-papilloma (P=0.0005) and choroid plexus-carcinoma (P=0.0001). Radiotherapy was associated with significantly better survival in choroid plexus-carcinomas. Eight of 22 documented choroid plexus-carcinomas responded to chemotherapy. Relapse after primary treatment was a poor prognostic factor in choroid plexus-carcinoma patients but not in choroid plexus-papilloma patients. Treatment of choroid plexus tumours should start with radical surgical resection. This should be followed by adjuvant treatment in case of choroid plexus-carcinoma, and a "wait and see" approach in choroid plexus-papilloma.

Adolescent↗

Salt-loading increases vasopressin and vasopressin 1b receptor mRNA in the hypothalamus and choroid plexus.

The choroid plexus plays a pivotal role in the production of cerebrospinal fluid (CSF). Messenger RNA (mRNA) transcripts encoding arginine vasopressin (AVP) and the vasopressin 1b receptor (V(1b)R) are found in various structures of the central nervous system, including the choroid plexus. The present study measured AVP and V(1b)R mRNA production in response to plasma hyperosmolality. Compared to rats maintained on water, 2% salt-drinking rats had increased levels of AVP and V(1b)R mRNAs in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus and in the choroid plexus. The increase in V(1b)R mRNA in the SON and PVN as a result of plasma hyperosmolality may reflect changes in receptor production that, in turn, have a role in AVP autoregulation of hypothalamic magnocellular neurons. The increase of AVP and V(1b)R mRNAs in the choroid plexus further shows the involvement of AVP in the regulation of brain water content and cerebral edema.

Animals↗

Physiological roles of aquaporins in the choroid plexus.

The choroid plexus is a specialized tissue that lines subdomains within the four ventricles of the brain where most of the cerebrospinal fluid is produced. Maintenance of an equilibrium in volume and composition of the cerebrospinal fluid (CSF) is vital for a normal brain function, ensuring an optimal environment for the neurons. The necessarily high water permeability of the choroid plexus barrier is made possible by the abundant expression of a water channel, Aquaporin-1 (AQP1), on the apical side of the membrane from early stages of development through adulthood. Data from studies of AQP1 suggest that it also can contribute as a gated ion channel, and suggest that the AQP1-mediated ionic conductance has physiological significance for the regulation of cerebrospinal fluid secretion. The regulation of AQP1 ion channels could be one of several transport mechanisms that contribute to the decreased CSF secretion in response to endogenous signaling molecules such as atrial natriuretic peptide. Numerous classes of ion channels and transporters are targeted specifically to each side of the cellular membrane, and they all work in concert to secrete CSF. Several signaling cascades have a direct effect on transporters and ion channels present in the choroid plexus epithelium, altering their transport activity and therefore modulating the net transcellular movement of solutes and water. Several neurotransmitters, neuropeptides, and growth factors can influence CSF secretion by direct effect on transport mechanisms of the epithelium. The mammalian choroid plexus receives innervation from noradrenergic sympathetic fibers, cholinergic and peptidergic fibers that modulate CSF secretion. Water imbalance in the brain can have life-threatening consequences resulting from altered excitability and neurodegeneration, disruption of the supply of nutrients, loss of signaling molecules, and the accumulation of unwanted toxins and metabolites. Understanding the mechanisms involved in the modulation of CSF secretion is of fundamental importance. An appreciation of AQP1 as an ion channel in addition to its role as a water channel should offer new targets for therapeutic strategies in diseases involving water imbalance in the brain.

Animals↗

Comparisons of HIV-1 viral sequences in brain, choroid plexus and spleen: potential role of choroid plexus in the pathogenesis of HIV encephalitis.

Possible mechanisms of HIV transmission to the brain include direct viral infection of cerebral endothelium and hematogeneous dissemination of viral-infected lymphocytes and monocytes. Cerebrospinal fluid dissemination from a primary infection of choroid plexus (CPx) is an alternative mechanism supported by recent studies in our laboratory. We showed that HIV-infected asymptomatic patients as well as AIDS patients have HIV infection of the CPx; the cell types so infected included stromal monocytes and dendritic cells. To further explore the potential role of CPx in the pathogenesis of HIV encephalitis, we analyzed HIV sequences from brain, CPx, and spleen of four AIDS patients by extracting DNA from paraffin sections and amplifying the V3 region of the HIV env gene by PCR. Several different clones from each tissue were characterized. We found that viruses from the brain and spleen grouped into two distinct clusters, while viruses of the CPx contained viral strains that were a mixture of those found in the brain or spleen. Net charge analysis of the V3 tip region showed that the brain viral sequences had fewer positive charges than blood viral sequences. Our results support the hypothesis that CPx may be one of the sites where HIV-1 gains access to the brain from the blood and therefore contains viruses that are of both genotypes.

AIDS Dementia Complex↗

Development of the choroid plexus.

Mammalian choroid plexuses develop at four sites in the roof of the neural tube shortly after its closure, in the order IVth, lateral, and IIIrd ventricles. Bone morphogenetic proteins and tropomyosin are involved in early specification of these sites and in early plexus growth. Four stages of lateral ventricular plexus development have been defined, based on human and sheep fetuses; these depend mainly on the appearance of epithelial cells and presence or absence of glycogen. Other plexuses and other species are probably similar, although marsupials may lack glycogen. Choroid plexuses form one of the blood-brain barrier interfaces that control the brain's internal environment. The mechanisms involved combine a structural diffusion restraint (tight junctions between the plexus epithelial cells) and specific exchange mechanisms. In this review, it is argued that barrier mechanisms in the developing brain are different in important respects from those in the adult brain, but these differences do not necessarily reflect immaturity of the system. Absence of a barrier mechanism or presence of one not found in the adult may be a specialisation that is appropriate for that stage of brain development. Emphasis is placed on determining which mechanisms are present in the immature brain and relating them to brain development. One mechanism unique to the developing brain transfers specific proteins from blood to cerebrospinal fluid (CSF), via tubulocisternal endoplasmic reticulum in plexus epithelial cells. This results in a high concentration of proteins in early CSF. These proteins do not penetrate into brain extracellular space because of "strap" junctions between adjacent neuroependymal cells, which disappear later in development, when the protein concentration in CSF is much lower. Functions of the proteins in early CSF are discussed in terms of generation of a "colloid" osmotic pressure that expands the ventricular system as the brain grows; the proteins may also act as specific carriers and growth factors in their own right. The pathway for low molecular weight compounds, which is much more permeable in the developing choroid plexuses, appears also to be a transcellular one, rather than paracellular via tight junctions. There is thus good evidence to support a novel view of the state of development and functional significance of barrier mechanisms in the immature brain. It grows in an environment that is different from that of the rest of the fetus/neonate and that is also different in some respects from that of the adult. But these differences reflect developmental specialisation rather than immaturity.

Animals↗

Monocyte-derived IL-10-secreting dendritic cells in choroid plexus epithelium.

Choroid plexuses form an interface between peripheral blood and cerebrospinal fluid. Dendritic-like cells have been reported in a few studies of choroid plexuses in man. Here we used electron microscopy and immunophenotyping to precise the morphologic features and phenotype of these cells. Examination of 10 human choroid plexuses evidenced intra-epithelial dendritic cells with a clear cytoplasm, reniform nucleus and long expansions. These cells express MHC Class II, CD11b, CD14, CD32, CD68 and IL-10, but not CD40, CD80 or CD86, suggesting an immunosuppressive role for these dendritic cells. Their sentinel position could make them participate to the immunological silence of the brain.

Aged↗

Potassium cotransport at the rat choroid plexus.

The choroid plexuses are involved in cerebrospinal fluid (CSF) secretion and CSF K homeostasis. We examined K transport mechanisms present in the isolated rat choroid plexus that may be involved in these functions, predominantly using 86Rb as a marker for K. The study demonstrates that there are two primary uptake mechanisms. Ouabain-sensitive Na-K-adenosinetriphosphatase and bumetanide-sensitive cotransport, probably of the Na-K-2Cl form, account for 48 and 46% of uptake, respectively. Efflux studies demonstrate that the primary K efflux mechanism is also bumetanide-sensitive cotransport with the other major component probably being by K channels as it is inhibitable by barium or quinidine. Efflux via the cotransporter was not inhibited by R(+)-butylindazone, a KCl cotransport inhibitor, but it was enhanced in the presence of ouabain (P < 0.001) or increased extracellular Na concentration (P < 0.01). Furthermore, Na efflux was bumetanide sensitive (P < 0.05). In all, these data suggest that the efflux cotransporter is also of the Na-K-Cl form and that it is the same transporter as the influx mechanism operating in both directions. The evidence presented leads us to hypothesize that this cotransporter is on the apical membrane of the choroid plexus and that it may have a central role in CSF secretion and perhaps CSF K homeostasis.

Animals↗

Rat choroid plexus specializes in the synthesis and the secretion of transthyretin (prealbumin). Regulation of transthyretin synthesis in choroid plexus is independent from that in liver.

Synthesis of total protein and of transthyretin in rat choroid plexus was studied by measuring the incorporation of radioactive leucine into proteins in choroid plexus tissue incubated in vitro. About 20% of the protein newly synthesized in choroid plexus and about 50% of the newly synthesized protein secreted into the medium was transthyretin. Evidently, the choroid plexus is very active in the biosynthesis of this carrier protein for thyroid hormones and could be an important link in the chemical communication between the body and the central nervous system. Acute inflammation, which leads to a profound rearrangement of the pattern of plasma protein synthesis rates in the liver, produced distinct changes in the levels for plasma protein mRNAs in the liver. The levels of the mRNAs for alpha 1-acid glycoprotein and major acute phase alpha 1-protein increased more than 30-fold, those for transthyretin and albumin decreased to 27 and 57% of normal, respectively. The pattern of the observed changes in the levels of mRNAs for plasma proteins in the liver was independent of whether the acute inflammation was produced by subcutaneous injection of turpentine or intraperitoneal injection of a suspension of talcum. However, levels of transthyretin mRNA in choroid plexus were affected only very slightly, or not at all. Apparently, transthyretin synthesis in liver and choroid plexus is regulated independently during the acute phase response. No mRNA was detected in choroid plexus for albumin, alpha 1-acid glycoprotein, and major acute phase alpha 1-protein under any conditions.

Animals↗

Magnetic resonance imaging in a dog with choroid plexus carcinoma.

Choroid plexus carcinoma was diagnosed in a 10-year-old maltese dog with chief complaint of progressive ataxia and head tilt. No abnormalities was observed on hemogram, radiographs of the skull, and electroencepharograph (EEG). Neurological examination suggested central vestibular lesions. On the magnetic resonance imaging (MRI) examination, images after contrast enhancement with Gadolinium DTPA-dimeglumine showed a rough circular lesion with an increased signal intensity in caudal fossa. This lesion was histopathologically confirmed to be choroid plexus carcinoma.

Animals↗