Abstract
The role of the choroid plexus (CP) in brain homeostasis is being increasingly recognized and recent studies suggest that the CP has a more important role in physiological and pathological brain functions than currently appreciated. To obtain additional insight on the CP function, we performed a proteomics and transcriptomics characterization employing a combination of high resolution tandem mass spectrometry and gene expression analyses in normal rodent brain. Using multiple protein fractionation approaches, we identified 1400 CP proteins in adult CP. Microarray-based comparison of CP gene expression with the kidney, cortex and hippocampus showed significant overlap between the CP and the kidney. CP gene profiles were validated by in situ hybridization analysis of several target genes including klotho, CLIC 6, OATP 14 and Ezrin. Immunohistochemical analyses were performed for CP and enpendyma detection of several target proteins including cytokeratin, Rab7, klotho, tissue inhibitor of metalloprotease 1 (TIMP1), MMP9 and glial fibrillary acidic protein (GFAP). The molecular functions associated with various proteins of the CP proteome indicate that it is a blood–cerebrospinal fluid (CSF) barrier that exhibits high levels of metabolic activity. We also analyzed the gene expression changes induced by stress, an exacerbating factor for many illnesses, particularly mood disorders. Chronic stress altered the expression of several genes, downregulating 5HT2C, glucocorticoid receptor and the cilia genes IFT88 and smoothened while upregulating 5HT2A, BDNF, TNFα and IL-1b. The data presented here attach additional significance to the emerging importance of CP function in brain health and CNS disease states.
Highlights
Two major CNS barriers regulate the movement of molecules between blood, brain and cerebrospinal fluid: the blood brain barrier (BBB) defined by cerebral vasculature, and the blood– cerebrospinal fluid (CSF) barrier (BCSFB) defined by the choroid plexus (CP)
In an effort to further understand the function and complexity of the mammalian choroid plexus, we examined global gene expression using an 18k rat microarray and compared the CP gene profile with the cortex, the hippocampus and the kidney
Functional classification of CP genes shows that it expresses molecules with diverse cellular functions, including multiple categories of receptors, transporters and carrier proteins
Summary
Two major CNS barriers regulate the movement of molecules between blood, brain and cerebrospinal fluid: the blood brain barrier (BBB) defined by cerebral vasculature, and the blood– cerebrospinal fluid (CSF) barrier (BCSFB) defined by the choroid plexus (CP). The CP has been primarily investigated for its role in CSF production and regulation of its composition,[1] recent work has demonstrated that the CP performs several additional functions, including CNS transport of peripheral trophic factors,[2] thyroid hormone distribution,[3] amyloid clearance,[4] micronutrient and vitamin transport,[5,6] protein synthesis[7] and neuroendocrine signaling.[8]. Structural analysis of the CP has shown that ageing and Alzheimer’s disease cause atrophy of the epithelial layer and alter CP function.[15,16]
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