Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zandl-Lang, M; Fanaee-Danesh, E; Sun, Y; Albrecher, NM; Gali, CC; Čančar, I; Kober, A; Tam-Amersdorfer, C; Stracke, A; Storck, SM; Saeed, A; Stefulj, J; Pietrzik, CU; Wilson, MR; Björkhem, I; Panzenboeck, U.
Regulatory effects of simvastatin and apoJ on APP processing and amyloid-β clearance in blood-brain barrier endothelial cells.
Biochim Biophys Acta Mol Cell Biol Lipids. 2018; 1863(1):40-60
Doi: 10.1016/j.bbalip.2017.09.008
Web of Science
PubMed
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FullText_MUG
- Führende Autor*innen der Med Uni Graz
- Panzenboeck Ute
- Zandl-Lang Martina
- Co-Autor*innen der Med Uni Graz
- Fanaee-Danesh Elham
- Gali Chaitanya Chakravarthi
- Kober Alexandra
- Stefulj Jasminka
- Stracke Anika
- Sun Yidan
- Tam-Amersdorfer Carmen
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- Abstract:
- Amyloid-β peptides (Aβ) accumulate in cerebral capillaries indicating a central role of the blood-brain barrier (BBB) in the pathogenesis of Alzheimer's disease (AD). Although a relationship between apolipoprotein-, cholesterol- and Aβ metabolism is evident, the interconnecting mechanisms operating in brain capillary endothelial cells (BCEC) are poorly understood. ApoJ (clusterin) is present in HDL that regulates cholesterol metabolism which is disturbed in AD. ApoJ levels are increased in AD brains and in plasma of cerebral amyloid angiopathy (CAA) patients. ApoJ may bind, prevent fibrillization, and enhance clearance of Aβ. We here define a connection of apoJ and cellular cholesterol homeostasis in amyloid precursor protein (APP) processing/Aβ metabolism at the BBB. Silencing of apoJ in primary porcine (p)BCEC decreased intracellular APP and Aβ oligomer levels while the addition of purified apoJ to pBCEC increased intracellular APP and enhanced Aβ clearance across the pBCEC monolayer. Treatment of pBCEC with Aβ(1-40) increased expression of apoJ and receptors involved in amyloid transport including lipoprotein receptor-related protein 1 [LRP1]. In accordance, cerebromicrovascular endothelial cells isolated from 3×Tg AD mice showed elevated expression levels of apoJ and LRP1 as compared to Non-Tg animals. Treatment of pBCEC with HMGCoA-reductase inhibitor simvastatin markedly increased intracellular and secreted apoJ levels, in parallel increased secreted Aβ oligomers and reduced Aβ uptake and cell-associated Aβ oligomers. Simvastatin effects on apoJ, APP processing, and LRP1 expression in BCEC were confirmed in the mouse model. We suggest a close and complex interaction of apoJ, cholesterol homeostasis, and APP/Aβ processing and clearance at the BBB. Copyright © 2017 Elsevier B.V. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Amyloid beta-Peptides - metabolism
- Amyloid beta-Protein Precursor - chemistry
- Amyloid beta-Protein Precursor - metabolism
- Animals -
- Blood-Brain Barrier - drug effects
- Blood-Brain Barrier - metabolism
- Cells, Cultured -
- Clusterin - pharmacology
- Endothelial Cells - drug effects
- Endothelial Cells - metabolism
- Female -
- Mice -
- Mice, Inbred C57BL -
- Mice, Transgenic -
- Peptide Fragments - metabolism
- Protein Processing, Post-Translational - drug effects
- Simvastatin - pharmacology
- Swine -
- Find related publications in this database (Keywords)
- Alzheimer disease
- Amyloid-beta (A beta)
- Endothelium
- Cholesterol metabolism
- Blood-brain barrier
- Clusterin/apoJ