Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-7918
Authors: | Freese, Christian Reinhardt, Sven Hefner, Gudrun Unger, Ronald E. Kirkpatrick, Charles James Endres, Kristina |
Title: | A novel blood-brain barrier co-culture System for drug targeting of Alzheimer’s disease : establishment by using acitretin as a model drug |
Online publication date: | 10-Oct-2022 |
Year of first publication: | 2014 |
Language: | english |
Abstract: | In the pathogenesis of Alzheimer’s disease (AD) the homeostasis of amyloid precursor protein (APP) processing in the brain is impaired. The expression of the competing proteases ADAM10 (a disintegrin and metalloproteinase 10) and BACE-1 (beta site APP cleaving enzyme 1) is shifted in favor of the A-beta generating enzyme BACE-1. Acitretin–a synthetic retinoid–e.g., has been shown to increase ADAM10 gene expression, resulting in a decreased level of A-beta peptides within the brain of AD model mice and thus is of possible value for AD therapy. A striking challenge in evaluating novel therapeutically applicable drugs is the analysis of their potential to overcome the blood-brain barrier (BBB) for central nervous system targeting. In this study, we established a novel cell-based bio-assay model to test ADAM10-inducing drugs for their ability to cross the BBB. We therefore used primary porcine brain endothelial cells (PBECs) and human neuroblastoma cells (SH-SY5Y) transfected with an ADAM10-promoter luciferase reporter vector in an indirect co-culture system. Acitretin served as a model substance that crosses the BBB and induces ADAM10 expression. We ensured that ADAM10-dependent constitutive APP metabolism in the neuronal cells was unaffected under co-cultivation conditions. Barrier properties established by PBECs were augmented by co-cultivation with SH-SY5Y cells and they remained stable during the treatment with acitretin as demonstrated by electrical resistance measurement and permeability-coefficient determination. As a consequence of transcellular acitretin transport measured by HPLC, the activity of the ADAM10-promoter reporter gene was significantly increased in co-cultured neuronal cells as compared to vehicle-treated controls. In the present study, we provide a new bio-assay system relevant for the study of drug |
DDC: | 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 04 Medizin FB 09 Chemie, Pharmazie u. Geowissensch. |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-7918 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | PLoS one 9 3 |
Pages or article number: | e91003 |
Publisher: | PLoS |
Publisher place: | Lawrence, Kan. |
Issue date: | 2014 |
ISSN: | 1932-6203 |
Publisher URL: | http://dx.doi.org/10.1371/journal.pone.0091003 |
Publisher DOI: | 10.1371/journal.pone.0091003 |
Appears in collections: | DFG-OA-Publizieren (2012 - 2017) |
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![]() | a_novel_bloodbrain_barrier_co-20220924204530824.pdf | 5.52 MB | Adobe PDF | View/Open |