AQP1 and AQP4 Contribution to Cerebrospinal Fluid Homeostasis

Trillo-Contreras, José Luis; Toledo‐Aral, Juan José; Echevarría, Miriam; Villadiego, Javier

doi:10.3390/cells8020197

Cited by 60 publications

(62 citation statements)

References 45 publications

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“…These observations also add to the experimental evidence suggesting that spinal cord formation of water adds to the CSF in supine subjects. Animal studies show that the water channel aquaporin-4 (AQP4), mediating a significant net extra-choroidal formation of CSF water, is abundant in brain and particularly the spinal cord tissue [ 41 ], where perivascular spaces communicate directly with subarachnoid CSF [ 42 , 43 ]. High rates of CSF secretion was previously shown from spinal cord ependyma [ 44 ], and a more recent study showed perivascular outflow of CSF from the entire spinal cord [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases

Eide

Valnes

Lindstrøm

et al. 2021

Fluids Barriers CNS

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Background Several central nervous system diseases are associated with disturbed cerebrospinal fluid (CSF) flow patterns and have typically been characterized in vivo by phase-contrast magnetic resonance imaging (MRI). This technique is, however, limited by its applicability in space and time. Phase-contrast MRI has yet to be compared directly with CSF tracer enhanced imaging, which can be considered gold standard for assessing long-term CSF flow dynamics within the intracranial compartment. Methods Here, we studied patients with various CSF disorders and compared MRI biomarkers of CSF space anatomy and phase-contrast MRI at level of the aqueduct and cranio-cervical junction with dynamic intrathecal contrast-enhanced MRI using the contrast agent gadobutrol as CSF tracer. Tracer enrichment of cerebral ventricles was graded 0–4 by visual assessment. An intracranial pressure (ICP) score was used as surrogate marker of intracranial compliance. Results The study included 94 patients and disclosed marked variation of CSF flow measures across disease categories. The grade of supra-aqueductal reflux of tracer varied, with strong reflux (grades 3–4) in half of patients. Ventricular tracer reflux correlated with stroke volume and aqueductal CSF pressure gradient. CSF flow in the cerebral aqueduct was retrograde (from 4th to 3rd ventricle) in one third of patients, with estimated CSF net flow volume about 1.0 L/24 h. In the cranio-cervical junction, net flow was cranially directed in 78% patients, with estimated CSF net flow volume about 4.7 L/24 h. Conclusions The present observations provide in vivo quantitative evidence for substantial variation in direction and magnitude of CSF flow, with re-direction of aqueductal flow in communicating hydrocephalus, and significant extra-cranial CSF production. The grading of ventricular reflux of tracer shows promise as a clinical useful method to assess CSF flow pattern disturbances in patients. Graphic abstract

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Section: Discussionmentioning

confidence: 99%

Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases

Eide

Valnes

Lindstrøm

et al. 2021

Fluids Barriers CNS

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“…Since we have observed that cpLECs may anatomically have greater access to the subarachnoid space than the other lymphatics, we next looked to see if they express any water transport proteins that might facilitate sampling of CSF. Aquaporins (AQPs) are often implicated in regulating fluid dynamics, with AQP-1 and AQP-4 most highly expressed in the CNS 41,42 . AQP-4 is expressed by astrocytic endfeet, hypothesized to regulate glymphatic function 43,44,45 , while AQP-1 is expressed on the apical membrane of the choroid plexus and is believed to be involved in CSF production 43 .…”

Section: Resultsmentioning

confidence: 99%

“…Aquaporins (AQPs) are often implicated in regulating fluid dynamics, with AQP-1 and AQP-4 most highly expressed in the CNS 41,42 . AQP-4 is expressed by astrocytic endfeet, hypothesized to regulate glymphatic function 43,44,45 , while AQP-1 is expressed on the apical membrane of the choroid plexus and is believed to be involved in CSF production 43 . Interestingly, a recent study by Norwood et al reported expression of AQP-1 near the cribriform plate, although the identity of the cell types that expressed AQP-1 was unknown 13 .…”

Section: Resultsmentioning

confidence: 99%

Neuroinflammation alters the phenotype of lymphangiogenic vessels near the cribriform plate

Hsu

Madrid

Choi

et al. 2020

Preprint

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Meningeal lymphatic vessels residing in the dural layer surrounding the dorsal regions of the brain, basal regions, and near the cribriform plate have all been implicated in the management of neuroinflammation and edema. Interestingly, only the lymphatic vessels near the cribriform plate undergo functional lymphangiogenesis in a mouse model of Multiple Sclerosis, suggesting these particular lymphatics uniquely undergo dynamic changes in response to neuroinflammation and may have distinct access to pro-lymphangiogenic factors in the CNS. However, it is unknown if these newly formed lymphangiogenic vessels are functionally similar to steady-state or if they have any other functional changes during neuroinflammation. In this study, we generated a novel protocol to isolate lymphatic endothelial cells from the cribriform plate for single cell analysis. We demonstrate that neuroinflammation-induced lymphangiogenic vessels undergo unique changes, including the capture of CNS-derived antigens, upregulation of adhesion and immune-modulatory molecules to interact with dendritic cells, and display IFN-γ dependent changes in response to the microenvironment. Single-cell trajectory analysis showed that cribriform plate lymphangiogenic vessels are post-proliferative and not generated from trans-differentiation of myeloid cells. Additionally, we show that these lymphangiogenic vessels have access to a CSF reservoir, express the water pore Aquaporin-1, and may have direct access to the CSF due to gaps in the arachnoid epithelial layer separating the dura from the subarachnoid space. These data characterize cribriform plate lymphatics and demonstrate that these vessels are dynamic structures that engage in leukocyte interactions, antigen sampling, and undergo expansion to drain excess fluid during neuroinflammation. Neuroinflammation not only induces efficient drainage of CSF but also alters the functions of lymphatic vessels near the cribriform plate.

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“…Choroidal and extrachoroidal CSF production/drainage, at least in experimental conditions, depend on aquaporin-1 and aquaporin-4 water channels, respectively (53,54). Here, we studied the expression patterns and intensities of aquaporin-1 in choroid plexuses as a read-out for putative alterations in choroid plexus functionality and CSF production.…”

Section: Discussionmentioning

confidence: 99%

Iron accumulation in the choroid plexus, ependymal cells and CNS parenchyma in a rat strain with low‐grade haemolysis of fragile macrocytic red blood cells

et al. 2021

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Iron accumulation in the CNS is associated with many neurological diseases via amplification of inflammation and neurodegeneration. However, experimental studies on iron overload are challenging, since rodents hardly accumulate brain iron in contrast to humans. Here, we studied LEWzizi rats, which present with elevated CNS iron loads, aiming to characterise choroid plexus, ependymal, CSF and CNS parenchymal iron loads in conjunction with altered blood iron parameters and, thus, signifying non-classical entry sites for iron into the CNS. Non-haem iron in formalin-fixed paraffin-embedded tissue was detected via DAB-enhanced Turnbull Blue stainings. CSF iron levels were determined via atomic absorption spectroscopy. Ferroportin and aquaporin-1 expression was visualised using immunohistochemistry. The analysis of red blood cell indices and serum/plasma parameters was based on automated measurements; the fragility of red blood cells was manually determined by the osmotic challenge. Compared with wild-type animals, LEWzizi rats showed strongly increased iron accumulation in choroid plexus epithelial cells as well as in ependymal cells of the ventricle lining. Concurrently, red blood cell macrocytosis, lowgrade haemolysis and significant haemoglobin liberation from red blood cells were apparent in the peripheral blood of LEWzizi rats. Interestingly, elevated iron accumulation was also evident in kidney proximal tubules, which share similarities with the blood-CSF barrier. Our data underscore the importance of iron gateways into the CNS other than the classical route across microvessels in the CNS parenchyma. Our findings of pronounced choroid plexus iron overload in conjunction with peripheral iron overload and increased RBC fragility in LEWzizi rats may be seminal for future studies of human diseases, in which similar constellations are found.

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AQP1 and AQP4 Contribution to Cerebrospinal Fluid Homeostasis

Cited by 60 publications

References 45 publications

Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases

Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases

Neuroinflammation alters the phenotype of lymphangiogenic vessels near the cribriform plate

Iron accumulation in the choroid plexus, ependymal cells and CNS parenchyma in a rat strain with low‐grade haemolysis of fragile macrocytic red blood cells

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