Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Waltl, S.
Die Effekte einer systemischen Entzündung auf die Lipid-Homeostase des zentralen Nervensystems
[ Dissertation ] Medical University of Graz; 2013. pp. 157
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- Autor*innen der Med Uni Graz:
- Waltl Sabine Evelyn
- Betreuer*innen:
- Levak Sanja
- Sattler Wolfgang
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- Abstract:
- Neuroinflammation is involved in the progression of several neurodegenerative diseases, like Alzheimer¿s disease, Parkinson¿s disease and Multiple sclerosis. I used a murine model of systemic inflammation and concomitant neuroinflammation to characterize transcriptional changes that underlie the physiological and pathophysiological effects of neuroinflammation. To investigate changes in gene expression upon peripherally induced neuroinflammation, a whole genome microarray was performed. I found pronounced changes in the regulation of genes involved in lipid metabolism, blood-brain barrier (BBB) function and inflammation. Furthermore, neuroinflammation mediated a strong upregulation of the transcript and protein levels of cholesterol 25-hydroxylase (CH25H). CH25H catalyzes the conversion from cholesterol to the more hydrophilic 25-hydroxycholesterol (25-HC). Two possible effects of increased 25-HC in the brain which I investigated here are modulation of BBB permeability and cholesterol homeostasis via liver X receptor (LXR) activation. I used an in vitro model of the BBB to evaluate the effect of 25-HC on cerebrovascular permeability and cell integrity. These experiments revealed that permeability and cell integrity decreased in a time-dependent manner. A comparison with the predominant end product of brain cholesterol elimination, namely 24-HC, demonstrated that both oxysterols affect permeability and cell integrity of porcine brain microvascular endothelial cells to a similar extent. In the second part of the study I sought to clarify effects of exogenously added 25-HC on transcriptional regulation of cholesterol biosynthetic genes, SREBP processing, and cholesterol biosynthesis in the murine CATH.a neuronal cell line as well as the astrocytoma cell line CCF-STTG1. I found that transcript levels of well known LXR target genes were regulated leading an upregulation of cholesterol dissimenating pathways and reduced transcripts of cholesterol biosynthetic pathways. This finding was supported by the fact, that the CATH.a neuronal cell line, treated with 25-HC showed a reduction of cholesterol biosynthesis in a concentration-dependent manner. Data of the present study indicate that neuroinflammation leads to pronounced changes in gene products of lipid metabolism, BBB integrity as well as inflammation. Furthermore, it shows that CH25H as well as its enzymatic endproduct 25-HC is upregulated under neuroinflammatory conditions in vivo and that 25-HC is a potent regulator of neuronal cholesterol homeostasis in vitro.