Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schweinzer, C.
Processing of APP in cerebrovascular endothelial cells - regulation by LXR agonists and altered cholesterol homeostasis
[ Dissertation ] Medical University of Graz; 2011. pp. 125
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- Autor*innen der Med Uni Graz:
- Schweinzer Cornelia Katrin
- Betreuer*innen:
- Panzenboeck Ute
- Sattler Wolfgang
- Wadsack Christian
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- Abstract:
- Impaired clearance of cerebral amyloid beta peptide (Aß) across the blood-brain barrier (BBB) may facilitate the onset and progression of Alzheimer¿s disease (AD). Additionally, experimental evidence suggests a central role for cellular cholesterol in amyloid protein precursor (APP) processing. The present study aimed to investigate whether brain capillary endothelial cells (BCEC; the anatomical basis of the BBB) are capable of endogenous APP synthesis and whether and to what extent APP synthesis and processing is under control of cellular cholesterol homeostasis. Intracellular cholesterol metabolism was pharmacologically manipulated by using natural and synthetic liver-X receptor (LXR) agonists. Using an in vitro model of the BBB consisting of primary porcine BCEC (pBCEC), we demonstrate that endogenous full-length APP synthesis by pBCEC is significantly increased while the amount of cell-associated, amyloidogenic Aß oligomers is decreased in response to 24(S)-hydroxycholesterol (24OH-C) or 27OH-C, TO901317, cholesterol, or simvastatin treatment. Oxysterols as well as simvastatin enhanced the secretion of non-amyloidogenic sAPP¿ up to 2.5-fold. In parallel, LXR agonists reduced cholesterol biosynthesis by 30-80% while stimulating esterification (up to 2.5-fold) and efflux (up to 2.5-fold) of cellular cholesterol by modifying HMG-CoA reductase (HMGCR), sterol regulatory element-binding protein (SREBP-2), acyl-coenzyme A:cholesterol acyltransferase (ACAT-2), and ATP binding cassette transporter A1 (ABCA1) expression levels. In a polarized in vitro model mimicking the BBB, pBCEC secreted sAPP¿ preferentially to the basolateral compartment. In summary, endothelial cells of the BBB actively synthesize APP, Aß oligomers, and secrete APP¿ in a polarized manner. APP processing by pBCEC is regulated by LXR agonists, which have been proven beneficial in experimental AD models. Characterization of the (apo)lipoprotein profile in pBCEC supernatants revealed that these cells secrete apoA-I and/or apoJ, major protein components of HDL-like particles formed at the BBB. Interestingly, both apolipoproteins were found in the same lipoprotein density fractions as sAPP¿, suggesting that apoA-I and apoJ may interact with sAPP¿, and the addition of apoA-I to pBCEC culture medium enhanced sAPP¿ production. Altogether our findings highlight the importance of gaining knowledge of the interplay between cholesterol, lipoprotein and APP/Aß metabolism at the blood-brain barrier.