Human choroid plexus is an uniquely involved area of the brain in amyloidosis: a histochemical, immunohistochemical and ultrastructural study

To better understand the characteristics of amyloid deposition in the choroid plexus, we examined autopsied brain by routine histology, immunohistochemistry, and electron microscopy in three group of patients: primary systemic amyloidosis (n=7), cerebral amyloid angiopathy (CAA, n=6), and controls (n=3). Three of the CAA patients had Alzheimer's disease. Congophilic, birefringent amyloid deposits of the choroid plexus were seen in six of the seven cases of systemic light chain amyloidosis. Immunohistochemistry revealed that the deposited amyloids had reactivity for immunoglobulin light chain and amyloid P component. Accumulation of macrophages labeled with monoclonal antibodies against CD 68 and major histocompatibility complex class II antigens were observed around the massive amyloid deposits. The presence of approximately 10 nm amyloid fibrils along the epithelial basement membrane as well as in the vascular walls was ascertained by electron microscopy. In CAA, Congo red-positive amyloid deposits were consistently present in meningeal blood vessels and were often found in senile plaques of the cerebral parenchyma; congophilic amyloid deposits were absent in the choroid plexus. Choroid plexus epithelial cells exhibited immunostaining for beta amyloid precursor protein (APP) with N-terminal- and C-terminal-specific antibodies; in particular, consistent staining was obtained for the latter antibody. Immunoreactivity for amyloid β protein (Aβ) with monoclonal antibodies (6E10, 4G8) was often found in choroid plexus epithelial cells. These findings suggest that amyloid deposition of the choroid plexus depends on the major component protein in amyloidosis, and that the choroid plexus may produce APP and Aβ protein although Aβ amyloidosis is not evident in the choroid plexus. ©1997 Elsevier Science B.V. All rights reserved.     

In situ formation of immune complexes in the choroid plexus of rats by sequential injection of a cationized antigen and unaltered antibodies

The deposition of cationized human serum albumin (HSAED) in the choroid plexus of rats was compared to deposition in renal glomeruli. Initial deposition in the choroid plexus required a higher dose of antigen than deposition in glomeruli. The optimal dose for deposition in the choroid plexus was 50 mg/kg of HSAED. With this dose the antigen was still present in the choroid plexus at eight days after injection, whereas the glomeruli became largely negative by one day. Immune complex formation and persistence was examined in the choroid plexus by injecting rabbit antibodies to HSA at varying times after the injection of HSAED. When a limited amount of antibody was injected, it localized preferentially to glomeruli as compared to the choroid plexus. When sufficient antibodies were injected, the antigen and antibodies persisted in a comparable manner in the choroid plexus and glomeruli. By the eighth day after injection of foreign proteins, rat IgG deposited in both organs, indicating an endogenous immune response. The formed deposits were still present at 28 days, containing HSA, rabbit IgG, and rat IgG, but not rat C3. These results indicate that immune deposits readily form in the choroid plexus after injecting a cationized antigen. Differences, however, exist in the formation of immune deposit in the choroid plexus and the glomeruli.     

Immune complex deposition in the choroid plexus of patients with acquired immunodeficiency syndrome

We identified immune complex deposits in the choroid plexus of approximately 75% of patients with acquired immunodeficiency syndrome (AIDS) who had either normal brains or human immunodeficiency virus encephalitis. Since circulating immune complexes are common in AIDS patients, and since local choroid plexus pathology usually was absent, their likely origin is from the bloodstream. Choroid plexus deposits of immune complexes have been implicated in altering the function of this structure or in enhancing its vulnerability to infection. Therefore, immune complex deposition in the choroid plexus of AIDS patients may be responsible for some of the common alterations in the cerebrospinal fluid and for the frequency of opportunistic infections in this region.     

Circumventricular organs in chronic serum sickness: a model for cerebral lupus

The pathogenesis of the CNS manifestations of systemic lupus erythematosus (SLE) has been the subject of considerable investigation. The focus of many of these studies has concerned immune complex deposition within the choroid plexus (CP). Involvement of the other brain fenestrated vascular beds, the small, paraventricular circumventricular organs, has not been ascertained. For this purpose, chronic serum sickness, a good immunopathological experimental model of naturally occurring systemic immunological disorders such as SLE, was induced in Wistar rats by prolonged immunization with bovine serum albumin (BSA). The involvement of circumventricular vascular beds by immune deposits was ascertained immunohistochemically. The choroid plexus was found to be the most intensely involved circumventricular structure. Immune complex deposits were also present, in descending order of frequency, in the area postrema, subfornical organ, and pineal gland.     

Molecular mechanism of distorted iron regulation in the blood-CSF barrier and regional blood-brain barrier following in vivo subchronic manganese exposure

Previous studies in this laboratory indicated that manganese (Mn) exposure in vitro increases the expression of transferrin receptor (TfR) by enhancing the binding of iron regulatory proteins (IRPs) to iron responsive element-containing RNA. The current study further tested the hypothesis that in vivo exposure to Mn increased TfR expression at both blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCB), which contributes to altered iron (Fe) homeostasis in the CSF. Groups of rats (10-11 each) received oral gavages at doses of 5 mg Mn/kg or 15 mg Mn/kg as MnCl(2) once daily for 30 days. Blood, CSF, and choroid plexus were collected and brain capillary fractions were separated from the regional parenchyma. Metal analyses showed that oral Mn exposure decreased concentrations of Fe in serum (-66%) but increased Fe in the CSF (+167%). Gel shift assay showed that Mn caused a dose-dependent increase of binding of IRP1 to iron responsive element-containing RNA in BCB in the choroid plexus (+70%), in regional BBB of capillaries of striatum (+39%), hippocampus (+56%), frontal cortex (+49%), and in brain parenchyma of striatum (+67%), hippocampus (+39%) and cerebellum (+28%). Real-time RT-PCR demonstrated that Mn exposure significantly increased the expression of TfR mRNA in choroid plexus and striatum with concomitant reduction in the expression of ferritin (Ft) mRNA. Collectively, these data indicate that in vivo Mn exposure results in Fe redistribution in body fluids through regulating the expression of TfR and ferritin at BCB and selected regional BBB. The disrupted Fe transport by brain barriers may underlie the distorted Fe homeostasis in the CSF.     

The immunopathophysiological effects of chronic serum sickness on rat choroid plexus, ciliary process and renal glomeruli.

The immunopathological findings and their effects upon the vascular permeability of the ciliary process, choroid plexus and renal glomeruli to intravenously injected 125I-bovine serum albumin (BSA) have been studied in 26 rats who survived a prolonged period of bovine serum albuminemia following the experimental chronic serum sickness model of Fennell and Pardo (8). Rat IgG and C3 and BSA were demonstrated in the experimental rats by direct immunofluorescence in glomeruli, ciliary process and choroid plexus of 85, 38 and 39 percent of animals respectively. Age and sex matched control tissues were negative. Statistically significant differences in the 125I-BSA content of urine, eye and brain were observed between the experimental and control groups. This experimental model offers an approach to the understanding of ocular and central nervous system involvement in clinical situations characterized by circulating immune complexes as well as an experimental tool with which to explore further the physiological consequences of immune deposits within the choroid plexus and ciliary body.     

Comprehensive lectin histochemistry of normal and neoplastic human choroid plexus cells: alternation of lectin-binding patterns through neoplastic transformation

Summary Lectin histochemistry of the normal and neoplastic human choroid plexus cells [six choroid plexus papillomas (CPPs) and three choroid plexus carcinomas (CPCs)] was performed using eight representative lectins to study the development of sugar chain structures and also to determine whether lectins were useful for a histopathological diagnosis of choroid plexus neoplasms (CPNs). The normal choroid plexus cells reacted with Ricinus communis (RCA-I), Canavalia ensiformis (Con A), Limax flavus (LFA) and Triticum vulgaris (WGA), while Arachis hypoaea (PNA) stained them only after the removal of sialic acid. Human fetal choroid plexus cells at 8 weeks gestation already showed the same lectin-binding patterns as adult ones. All CPNs were stained by RCA-I and Con A in a similar manner as the normal choroid plexus cells. Although seven CPNs were positive for LFA, two CPCs were not stained by LFA, which bound to sialic acid. Two LFA-positive CPPs were stained by PNA before the removal of sialic acid. Moreover, unlike the normal choroid plexus cells, Ulex europaeus-, Glycine maximus- and Dolichos biflorus- binding sites often appeared, and WGA-binding sites of three CPNs remained even after sialic acid removal. In conclusion, the glycosialylation in normal choroid plexus cells was completed during the early embryonic stage. The lectin-binding patterns of CPNs were heterogenous in each case. The alternation of the glycosialylation and/or acquisition of binding sites for some lectins was sometimes observed through a neoplastic transformation.     

Serotonin 5-HT1C receptors are expressed at high density on choroid plexus tumors from transgenic mice

Choroid plexus tumors develop spontaneously in adult transgenic mice carrying integrated copies of SV40 early region genes. In this communication, we report that these tumors exhibit the highest density of serotonin receptors (6600 fmol/mg protein) found in any tissue. ¹²⁵I-LSD binding to choroid plexus tumors displays a pharmacological profile that matches the properties of 5-HT_1C receptors in normal choroid plexus tissue. Autoradiographic localization of ¹²⁵I-LSD binding in brain sections from transgenic mice shows high levels of labelling in the tumors, in correlation with immunohistochemical staining for SV40 large T antigen expression. Choroid plexus tumors from these transgenic mice provide an excellent model system for the study of serotonin 5-HT_1C receptors.     

Immunohistochemical study of insulin-like growth factor II (IGF-II) and insulin-like growth factor binding protein-2 (IGFBP-2) in choroid plexus papilloma

Abstract

Insulin-like growth factor-ll (IGF-II), a mitogen for various kinds of cells, has been shown to be secreted from the choroid plexus in animals. Insulin-like growth factor binding protein-2 (IGFBP-2), one of the six carrier proteins for IGFs, is also thought to be released from the choroid plexus, bind to IGF-II in the cerebrospinal fluid (CSF) and modulate the action of this growth factor. Little is known about the expression and localization of these substances in human choroid plexus and choroid plexus papillomas. The present immunohistochemical study demonstrated all six choroid plexus papillomas were positive for IGF-II, whereas normal choroid plexuses were negative for IGF-II. On the other hand, IGFBP-2 was positive in the endothelium and vascular media in the normal choroid plexus, while it was weakly positive in four and negative in two out of six choroid plexus papillomas. These results suggest that the alterations in the IGF-II/ IGFBP-2 axis might be involved in the tumorigenesis of choroid plexus papilloma. [Neurol Res 1999; 21: 339-344]     

Kinetic analysis of glutamate transport by the miniswine choroid plexus in vitro

Transport of glutamic acid by the choroid plexus, the blood-cerebrospinal fluid (CSF) barrier, was investigated by using the isolated choroid plexi from the fourth (FVCP) and lateral ventricles (LVCP) of the young adult miniswine in vitro. Glutamic acid uptake was very pronounced, with concentrations 7-fold (LVCP) and 2.4-fold (FVCP) higher in tissue than in medium after only 5 min of incubation with 1 μM glutamic acid. Tissue/medium ratios reached steady state by 15 min at 30-fold (LVCP) and 11-fold (FVCP). Uptake was energy-dependent and inhibited by ouabain and hypothermia.l-Aspartic acid was shown to be inhibitory in a concentration-dependent manner, suggesting that it shares a common transport system, whereas neither octanoic acid nor okadaic acid (transported by a separate fatty acid system) inhibited glutamic acid transport. At the same temperature, the labeled metabolite of glutamate (glutamine) in the tissue was 64.7%, 73.2%, and 72.5% of total radioactivity at 5, 30, and 60 min, respectively. The estimatedK_m values for glutamate uptake by the choroid plexus are 264 μM (FVCP) and 196 μM (LVCP);V_max values are 87 (FVCP) and 147 (LVCP) nmol/g/min, respectively. These results indicate that, in addition to the metabolism of glutamate to glutamine, an active uptake mechanism is present in the choroid plexus of miniswine which may serve to regulate glutamic acid concentration in the CSF.