TY - JOUR

T1 - The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier

AU - Kurtyka, Magdalena

AU - Wessely, Frank

AU - Bau, Sarah

AU - Ifie, Eseoghene

AU - He, Liqun

AU - de Wit, Nienke M.

AU - Pedersen, Alberte Bay Villekjær

AU - Keller, Maximilian

AU - Webber, Caleb

AU - de Vries, Helga E.

AU - Ansorge, Olaf

AU - Betsholtz, Christer

AU - De Bock, Marijke

AU - Chaves, Catarina

AU - Brodin, Birger

AU - Nielsen, Morten S.

AU - Neuhaus, Winfried

AU - Bell, Robert D.

AU - Letoha, Tamás

AU - Meyer, Axel H.

AU - Leparc, Germán

AU - Lenter, Martin

AU - Lesuisse, Dominique

AU - Cader, Zameel M.

AU - Buckley, Stephen T.

AU - Loryan, Irena

AU - Pietrzik, Claus U.

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024

Y1 - 2024

N2 - Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBB-enriched genes according to established selection criteria. As a result, we propose the high-affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1-specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB.

AB - Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBB-enriched genes according to established selection criteria. As a result, we propose the high-affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1-specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB.

KW - BBB

KW - brain drug delivery

KW - brain therapeutics

KW - CAT-1

KW - SLC7A1

KW - solute carriers

U2 - 10.1016/j.ejcb.2024.151406

DO - 10.1016/j.ejcb.2024.151406

M3 - Journal article

C2 - 38547677

AN - SCOPUS:85189017595

VL - 103

JO - Cytobiologie

JF - Cytobiologie

SN - 0724-5130

IS - 2

M1 - 151406

ER -