Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Schweinzer, C; Kober, A; Lang, I; Etschmaier, K; Scholler, M; Kresse, A; Sattler, W; Panzenboeck, U.
Processing of endogenous AβPP in blood-brain barrier endothelial cells is modulated by liver-X receptor agonists and altered cellular cholesterol homeostasis.
J Alzheimers Dis. 2011; 27(2):341-360
Doi: 10.3233/JAD-2011-110854
Web of Science
PubMed
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- Führende Autor*innen der Med Uni Graz
- Panzenboeck Ute
- Schweinzer Cornelia Katrin
- Co-Autor*innen der Med Uni Graz
- Etschmaier Karoline
- Kober Alexandra
- Kresse Adelheid
- Lang-Olip Ingrid
- Sattler Wolfgang
- Scholler Monika
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- Abstract:
- Impaired clearance of cerebral amyloid-β (Aβ) 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-β protein precursor (AβPP) processing. The present study investigated whether brain capillary endothelial cells (BCEC; the anatomical basis of the BBB) are capable of endogenous AβPP synthesis and whether and to what extent AβPP 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 AβPP synthesis by pBCEC is significantly increased while the amount of cell-associated, amyloidogenic Aβ 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 sAβPPα 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 hydroxymethylglutaryl-CoA reductase (HMGCR), sterol regulatory element-binding protein (SREBP-2), acyl-CoA: cholesterol acyltransferase 2 (ACAT-2), and ATP binding cassette transporter A1 (ABCA1) expression levels. In a polarized in vitro model mimicking the BBB, pBCEC secreted sAβPPα preferentially to the basolateral compartment. In summary endothelial cells of the BBB actively synthesize AβPP, Aβ oligomers, and secrete AβPPα in a polarized manner. AβPP processing by pBCEC is regulated by LXR agonists, which have been proven beneficial in experimental AD models.
- Find related publications in this database (using NLM MeSH Indexing)
- Amyloid beta-Protein Precursor - metabolism
- Animals -
- Blood-Brain Barrier - drug effects
- Cells, Cultured -
- Cholesterol - metabolism
- Endothelial Cells - drug effects
- Homeostasis - drug effects
- Humans -
- Lipid Metabolism - drug effects
- Orphan Nuclear Receptors - agonists
- Protein Processing, Post-Translational - drug effects
- Simvastatin - pharmacology
- Swine -
- Find related publications in this database (Keywords)
- Alzheimer's disease
- amyloid-beta
- blood-brain barrier
- cholesterol
- endothelial cells
- liver-X receptors
- oxysterols
- statins