scholarly journals Localization of the Folate Transport Systems in the Murine Central Nervous System

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 922-922
Author(s):  
Vishal Sangha ◽  
Md. Tozammel Hoque ◽  
Jeffrey Henderson ◽  
Reina Bendayan
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Folate Receptor ◽  
Brain Parenchyma ◽  
Receptor Expression ◽  
Transport Systems ◽  
Folate Transport ◽  
Engineering Research ◽  
Receptor Localization ◽  
Brain Barriers

Abstract Objectives Folates are critical for normal neurodevelopment, and folate transport in the brain is primarily mediated by folate receptor alpha (FRα) at the blood-cerebrospinal fluid barrier (BCSFB). However, studies have reported folate transporter/receptor expression in other brain compartments, which may significantly contribute to overall brain folate uptake. The objective of this study is to characterize the localization of the folate transport systems i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and FRα in the mouse central nervous system, which will provide insight on novel routes of brain folate transport. In particular, folate transporter/receptor localization is examined at brain barriers [blood-brain barrier (BBB), BCSFB, arachnoid barrier (AB)] and in brain parenchyma (astrocytes, microglia, neurons). Methods The localization of RFC, PCFT and FRα was observed in the brains of C57BL6/N wildtype mice by applying immunohistochemistry (IHC). Mouse brains were isolated, and IHC was performed on frozen coronal sections. Transporter/receptor localization was examined at brain barriers (BBB, BCSFB, AB) and in brain parenchyma (astrocytes, neurons, microglia) using specific antibodies. Standard IHC markers were utilized to identify various brain compartments, with confocal microscopy used for imaging. Results At the mouse BBB and BCSFB, localization of RFC, PCFT and FRα was observed, which is consistent with previous reported data and our own work. At the AB, in astrocytes and neurons localization of RFC and PCFT (but not FRα) was observed. In microglia, no expression of the folate transporters or receptor was detected. Conclusions RFC and PCFT localization at the AB may represent a novel route of folate transport into the CSF, with transporter expression in neurons and astrocytes facilitating folate uptake into brain parenchyma cellular targets. Modulating folate transport at these brain compartments may provide a novel strategy in increasing brain folate uptake in disorders associated with defective FRα and impaired brain folate transport at the BCSFB. Funding Sources This work is supported by the Natural Sciences and Engineering Research Council of Canada (RB). VS is a recipient of several graduate scholarships.

scholarly journals Exosomes as cell-derivative carriers in the diagnosis and treatment of central nervous system diseases

2021 ◽  
Author(s):  
Gayatri Gopal Shetgaonkar ◽  
Shirleen Miriam Marques ◽  
Cleona E. M. DCruz ◽  
R. J. A. Vibhavari ◽  
Lalit Kumar ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Parenchyma ◽  
Brain Diseases ◽  
Nervous System Diseases ◽  
Central Nervous System Diseases ◽  
Diagnosis And Prognosis ◽  
Potential Biomarker ◽  
Treatment And Diagnosis ◽  
The Brain

AbstractExosomes are extracellular vesicles with the diameter ranging from 50 to 100 nm and are found in different body fluids such as blood, cerebrospinal fluid (CSF), urine and saliva. Like in case of various diseases, based on the parent cells, the content of exosomes (protein, mRNA, miRNA, DNA, lipids and metabolites) varies and thus can be utilized as potential biomarker for diagnosis and prognosis of the brain diseases. Furthermore, utilizing the natural potential exosomes to cross the blood–brain barrier and by specifically decorating it with the ligand as per the desired brain sites therapeutics can be delivered to brain parenchyma. This review article conveys the importance of exosomes and their use in the treatment and diagnosis of brain/central nervous system diseases. Graphical abstract

Glial Function in Homeostasis of the Neuronal Microenvironment

Physiology ◽  
1994 ◽  
Vol 9 (6) ◽  
pp. 265-267
Author(s):  
RK Orkand ◽  
SC Opava
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Small Molecules ◽  
Transport Systems ◽  
Large Area ◽  
Glial Function ◽  
The Central Nervous System ◽  
Glial Membrane ◽  
Membrane Transport Systems ◽  
Specific Membrane

Neuroglia buffer changes in the concentrations of ions and small molecules in the tortuous network of narrow extracellular clefts that constitutes the functional environment of neurons in the central nervous system. The large area of glial membrane bordering this space exhibits specific membrane transport systems for homeostasis.

scholarly journals Immune System in the Brain: A Modulatory Role on Dendritic Spine Morphophysiology?

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Oscar Kurt Bitzer-Quintero ◽  
Ignacio González-Burgos
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune System ◽  
Dendritic Spines ◽  
Cell Lineage ◽  
Myeloid Cell ◽  
Brain Parenchyma ◽  
Immune Mediators ◽  
The Central Nervous System ◽  
The Brain

The central nervous system is closely linked to the immune system at several levels. The brain parenchyma is separated from the periphery by the blood brain barrier, which under normal conditions prevents the entry of mediators such as activated leukocytes, antibodies, complement factors, and cytokines. The myeloid cell lineage plays a crucial role in the development of immune responses at the central level, and it comprises two main subtypes: (1) resident microglia, distributed throughout the brain parenchyma; (2) perivascular macrophages located in the brain capillaries of the basal lamina and the choroid plexus. In addition, astrocytes, oligodendrocytes, endothelial cells, and, to a lesser extent, neurons are implicated in the immune response in the central nervous system. By modulating synaptogenesis, microglia are most specifically involved in restoring neuronal connectivity following injury. These cells release immune mediators, such as cytokines, that modulate synaptic transmission and that alter the morphology of dendritic spines during the inflammatory process following injury. Thus, the expression and release of immune mediators in the brain parenchyma are closely linked to plastic morphophysiological changes in neuronal dendritic spines. Based on these observations, it has been proposed that these immune mediators are also implicated in learning and memory processes.

scholarly journals Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha

2019 ◽  
Vol 116 (35) ◽  
pp. 17531-17540 ◽  
Author(s):  
Camille Alam ◽  
Susanne Aufreiter ◽  
Constantine J. Georgiou ◽  
Md. Tozammel Hoque ◽  
Richard H. Finnell ◽  
...  
Keyword(s):  
Vitamin D ◽  
Choroid Plexus ◽  
Folate Receptor ◽  
Functional Expression ◽  
Transport Systems ◽  
Reduced Folate Carrier ◽  
Folate Transport ◽  
Folate Receptor Alpha ◽  
Receptor Alpha ◽  
Neurometabolic Disorders

Folates are critical for central nervous system function. Folate transport is mediated by 3 major pathways, reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRα/Folr1), known to be regulated by ligand-activated nuclear receptors. Cerebral folate delivery primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems can result in very low folate levels in the cerebrospinal fluid causing childhood neurodegenerative disorders. These disorders have devastating effects in young children, and current therapeutic approaches are not sufficiently effective. Our group has previously reported in vitro that functional expression of RFC at the blood–brain barrier (BBB) and its upregulation by the vitamin D nuclear receptor (VDR) could provide an alternative route for brain folate uptake. In this study, we further demonstrated in vivo, using Folr1 knockout (KO) mice, that loss of FRα led to a substantial decrease of folate delivery to the brain and that pretreatment of Folr1 KO mice with the VDR activating ligand, calcitriol (1,25-dihydroxyvitamin D3), resulted in over a 6-fold increase in [13C5]-5-formyltetrahydrofolate ([13C5]-5-formylTHF) concentration in brain tissues, with levels comparable to wild-type animals. Brain-to-plasma concentration ratio of [13C5]-5-formylTHF was also significantly higher in calcitriol-treated Folr1 KO mice (15-fold), indicating a remarkable enhancement in brain folate delivery. These findings demonstrate that augmenting RFC functional expression at the BBB could effectively compensate for the loss of Folr1-mediated folate uptake at the choroid plexus, providing a therapeutic approach for neurometabolic disorders caused by defective brain folate transport.

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