The Endo-Lysosomal System of Brain Endothelial Cells Is Influenced by Astrocytes In Vitro

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  • Andrea E Toth
  • Piotr Siupka, Lundbeck Foundation, Research Initiative on Brain Barriers and Drug Delivery, Scherfigsvej 7, 2100, Copenhagen, Denmark.
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  • Thomas J P Augustine, Research Program for Molecular Neurology, Helsinki University, Haartmaninkatu 8, 00290, Helsinki, Finland.
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  • Susanne T Venø, Lundbeck Foundation, Research Initiative on Brain Barriers and Drug Delivery, Scherfigsvej 7, 2100, Copenhagen, Denmark.
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  • Louiza B Thomsen, Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 3, 9220, Aalborg, Denmark.
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  • Torben Moos, Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 3, 9220, Aalborg, Denmark.
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  • Hannes T Lohi, Research Program for Molecular Neurology, Helsinki University, Haartmaninkatu 8, 00290, Helsinki, Finland.
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  • Peder Madsen
  • Karin Lykke-Hartmann
  • Morten S Nielsen

Receptor- and adsorptive-mediated transport through brain endothelial cells (BEC) of the blood-brain barrier (BBB) involves a complex array of subcellular vesicular structures, the endo-lysosomal system. It consists of several types of vesicles, such as early, recycling, and late endosomes, retromer-positive structures, and lysosomes. Since this system is important for receptor-mediated transcytosis of drugs across brain capillaries, our aim was to characterise the endo-lysosomal system in BEC with emphasis on their interactions with astrocytes. We used primary porcine BEC in monoculture and in co-culture with primary rat astrocytes. The presence of astrocytes changed the intraendothelial vesicular network and significantly impacted vesicular number, morphology, and distribution. Additionally, gene set enrichment analysis revealed that 60 genes associated with vesicular trafficking showed altered expression in co-cultured BEC. Cytosolic proteins involved in subcellular trafficking were investigated to mark transport routes, such as RAB25 for transcytosis. Strikingly, the adaptor protein called AP1-μ1B, important for basolateral sorting in epithelial cells, was not expressed in BEC. Altogether, our data pin-point unique features of BEC trafficking network, essentially mapping the endo-lysosomal system of in vitro BBB models. Consequently, our findings constitute a valuable basis for planning the optimal route across the BBB when advancing drug delivery to the brain.

OriginalsprogEngelsk
TidsskriftMolecular Neurobiology
Vol/bind55
Nummer11
Sider (fra-til)8522-8537
Antal sider16
ISSN0893-7648
DOI
StatusUdgivet - nov. 2018

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