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An Immunohistopathologic Study to Profile the Folate Receptor Beta Macrophage and Vascular Immune Microenvironment in Giant Cell Arteritis
Published on: February 8, 2019
Altered folate binding protein expression and folate delivery are associated with congenital hydrocephalus in the
Alicia Requena Jimenez1, Naila Naz1, Jaleel A Miyan1
1Faculty of Biology, Medicine & Health, Division of Neuroscience & Experimental Psychology, The University of Manchester, Manchester, UK.
Insights
Depletion of 10-formyl-tetrahydrofolate-dehydrogenase (FDH) in cerebrospinal fluid (CSF) halts brain cell growth in hydrocephalus (HC). FDH regulates folate to control arachnoid cell division, crucial for fluid absorption.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Hydrocephalus (HC) involves cerebrospinal fluid (CSF) imbalance, leading to brain fluid accumulation and pathology.
- A unique cerebral folate system's role in HC pathophysiology is under investigation.
Purpose of the Study:
- To investigate the role of 10-formyl-tetrahydrofolate-dehydrogenase (FDH) and the cerebral folate system in hydrocephalus.
- To determine the impact of CSF folate levels on arachnoid and cortical progenitor cell proliferation in HC.
Main Methods:
- Tissue culture, immunohistochemistry, in-situ PCR, and RT-PCR were employed.
- Experiments involved analyzing CSF from hydrocephalic Texas (H-Tx) rats and its effect on cell proliferation.
- FDH, folate-receptor-alpha (FRα), and folate levels were quantified and manipulated.
Main Results:
- Depletion of CSF FDH in H-Tx rats correlated with cortical progenitor cell-cycle arrest.
- In vitro, arachnoid cell proliferation was folate-dependent and exacerbated by HC-CSF with low FDH but high FRα and folate.
- Adding FDH to HC-CSF normalized aberrant arachnoid cell proliferation, indicating FDH's regulatory role.
Conclusions:
- Abnormal CSF levels of FDH, FRα, and folate impair cortical cell proliferation in HC.
- Uncontrolled arachnoid cell division occurs in HC, potentially to enhance fluid absorption, but this mechanism fails.
- FDH acts as a folate buffer, regulating arachnoid cell proliferation and function in the cerebral folate system.
Abstract:
Hydrocephalus (HC) is an imbalance in cerebrospinal fluid (CSF) secretion/absorption resulting in fluid accumulation within the brain with consequential pathophysiology. Our research has identified a unique cerebral folate system in which depletion of CSF 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is associated with cortical progenitor cell-cycle arrest in hydrocephalic Texas (H-Tx) rats. We used tissue culture, immunohistochemistry, in-situ PCR and RT-PCR and found that the in-vitro proliferation of arachnoid cells is highly folate-dependent with exacerbated proliferation occurring in hydrocephalic CSF that has low FDH but high folate-receptor-alpha (FRα) and folate. Adding FDH to this CSF prevented aberrant proliferation indicating a regulatory function of FDH on CSF folate concentration. Arachnoid cells have no detectable mRNA for FRα or FDH, but FDH mRNA is found in the choroid plexus (CP) and CSF microvesicles. Co-localization of FDH, FRα and folate suggests important functions of FDH in cerebral folate transport, buffering and function. In conclusion, abnormal CSF levels of FDH, FRα and folate inhibit cortical cell proliferation but allow uncontrolled arachnoid cell division that should increase fluid absorption by increasing the arachnoid although this fails in the hydrocephalic brain. FDH appears to buffer available folate to control arachnoid proliferation and function.
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