Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Aβ) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer’s disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: β-amyloid (Aβ) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Aβ in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Aβ42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Aβ transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Aβ burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Aβ) and diminished secretion of TTR (less neuroprotection against cortical Aβ toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD.

BackgroundAquaporin-4 (AQP4) is a water channel mainly located in the ventricular ependymal cells (brain-CSF barrier), the sub-ependymal glia, glia limitans and in end-feet of astrocytes in at the blood–brain barrier (BBB).MethodsIn the present work, the expression of AQP4 in the cerebrospinal fluid (CSF) in control and congenital human hydrocephalus infants (obstructive and communicating), was analysed by Western-blot and enzyme immunoassay (ELISA).ResultsAQP4 was found to be high compared to the control in the CSF in congenital hydrocephalus patients. Western-blot showed higher values for AQP4 than controls in communicating hydrocephalus (communicating: 38.3%, control: 6.9% p < 0.05) although the increase was not significant in obstructive hydrocephalus (obstructive: 14.7%). The AQP4 quantification by ELISA also showed that, the mean concentration of AQP4 in CSF was significantly higher in communicating hydrocephalus (communicating: 11.32 ± 0.69 ng/ml, control: 8.61 ± 0.31 ng/ml; p < 0.05). However, there was no increase over control in obstructive hydrocephalus (obstructive: 8.65 ± 0.80 ng/ml).ConclusionsAQP4 has a modulatory effect on ependyma stability and acts in CSF production and reabsorption. Therefore, the increase of AQP4 in the CSF in congenital hydrocephalus could be due to the fact that AQP4 passes from the parenchyma to the CSF and this AQP4 movement may be a consequence of ependyma denudation.

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Hydrocephalus is a distension of the ventricular system associated with ventricular zone disruption, reactive astrogliosis, periventricular white matter ischemia, axonal impairment, and corpus callosum alterations. The condition's etiology is typically attributed to a malfunction in classical cerebrospinal fluid (CSF) bulk flow; however, this approach does not consider the unique physiology of CSF in fetal and perinatal patients. The parenchymal fluid contributes to the glymphatic system, and plays a fundamental role in pediatric hydrocephalus, with aquaporin 4 (AQP4) as the primary facilitator of these fluid movements. Despite the importance of AQP4 in the pathophysiology of hydrocephalus, it’s expression in human fetal life is not well-studied. This manuscript systematically defines the brain expression of AQP4 in human brain development under control (n = 13) and hydrocephalic conditions (n = 3). Brains from 8 postconceptional weeks (PCW) onward and perinatal CSF from control (n = 2), obstructive (n = 6) and communicating (n = 6) hydrocephalic samples were analyzed through immunohistochemistry, immunofluorescence, western blot, and flow cytometry. Our results indicate that AQP4 expression is observed first in the archicortex, followed by the ganglionic eminences and then the neocortex. In the neocortex, it is initially at the perisylvian regions, and lastly at the occipital and prefrontal zones. Characteristic astrocyte end-feet labeling surrounding the vascular system was not established until 25 PCW. We also found AQP4 expression in a subpopulation of glial radial cells with processes that do not progress radially but, rather, curve following white matter tracts (corpus callosum and fornix), which were considered as glial stem cells (GSC). Under hydrocephalic conditions, GSC adjacent to characteristic ventricular zone disruption showed signs of early differentiation into astrocytes which may affect normal gliogenesis and contribute to the white matter dysgenesis. Finally, we found that AQP4 is expressed in the microvesicle fraction (p < 0.01) of CSF from patients with obstructive hydrocephalus. These findings suggest the potential use of AQP4 as a diagnostic and prognostic marker of pediatric hydrocephalus and as gliogenesis biomarker.

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The aim of the present work is to analyze the cerebrospinal fluid proteomic profile, trying to find possible biomarkers of the effects of hypertension of the blood to CSF barrier disruption in the brain and their participation in the cholesterol and β-amyloid metabolism and inflammatory processes. Cerebrospinal fluid (CSF) is a system linked to the brain and its composition can be altered not only by encephalic disorder, but also by systemic diseases such as arterial hypertension, which produces alterations in the choroid plexus and cerebrospinal fluid protein composition. 2D gel electrophoresis in cerebrospinal fluid extracted from the cistern magna before sacrifice of hypertensive and control rats was performed. The results showed different proteomic profiles between SHR and WKY, that α-1-antitrypsin, apolipoprotein A1, albumin, immunoglobulin G, vitamin D binding protein, haptoglobin and α-1-macroglobulin were found to be up-regulated in SHR, and apolipoprotein E, transthyretin, α-2-HS-glycoprotein, transferrin, α-1β-glycoprotein, kininogen and carbonic anhidrase II were down-regulated in SHR. The conclusion made here is that hypertension in SHR produces important variations in cerebrospinal fluid proteins that could be due to a choroid plexus dysfunction and this fact supports the close connection between hypertension and blood to cerebrospinal fluid barrier disruption.

Glioblastoma (GBM) is the most malignant tumor in the brain. In addition to the vascular pattern with thin-walled vessels and findings of sprouting angiogenesis, GBM presents a bizarre microvasculature (BM) formed by vascular clusters, vascular garlands, and glomeruloid bodies. The mechanisms in BM morphogenesis are not well known. Our objective was to assess the role of pericyte/endothelial proliferation and intussusceptive angiogenic mechanisms in the formation of the BM. For this purpose, we studied specimens of 66 GBM cases using immunochemistry and confocal microscopy. In the BM, the results showed (a) transitional forms between the BM patterns, mostly with prominent pericytes covering all the abluminal endothelial cell (EC) surface of the vessels, (b) a proliferation index high in the prominent pericytes and low in ECs (47.85 times higher in pericytes than in ECs), (c) intravascular pillars (hallmark of intussusceptive angiogenesis) formed by transcapillary interendothelial bridges, endothelial contacts of opposite vessel walls, and vessel loops, and (d) the persistence of these findings in complex glomeruloid bodies. In conclusion, disproportion in pericyte/EC proliferation and mechanisms of intussusceptive angiogenesis participate in BM formation. The contributions have morphogenic and clinical interest since pericytes and intussusceptive angiogenesis can condition antiangiogenic therapy in GBM.

High blood pressure produces ventricular dilation, variations in circumventricular organs and changes in the cerebrospinal fluid compositions. On the other hand, chronic hypertension in spontaneously hypertensive rats can cause changes in the integrity of the brain barriers: blood-cerebrospinal fluid barrier and blood brain barrier. The permeability of the brain barriers can be studied by using transthyretin and S-100β. In the present work we study the integrity of the brain barrier and the choroid plexus function variations in arterial hypertension. Control rats and spontaneously hypertensive rats were used and the choroid plexus were processed by immunohistochemistry with anti-transthyretin and anti-vasopressin. Western blot was also performed in cerebrospinal fluid, serum and choroid plexus using anti-S-100β, anti-transthyretin. The accumulation of transthyretin immunoreactive was bigger in spontaneously hypertensive rats with respect to the control. Vasopressin was also higher in spontaneously hypertensive rats with respect to the control. Western blot showed that transthyretin tetramer was higher in the spontaneously hypertensive rats than in the control rats. The expression of transthyretin monomer was lower in hypertensive rats than the control in the cerebrospinal fluid, the transthyretin monomer reaction in the blood was stronger in hypertensive than in control rats. Western blot for the S-100 β showed an increase in blood and cerebrospinal fluid of hypertensive rats. The high blood pressure produces a disruption of the blood brain barrier and blood to cerebrospinal fluid barrier that allows extravasations from the cerebrospinal fluid to the blood and from the blood to the cerebrospinal fluid