Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma
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Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. / Grapp, Marcel; Wrede, Arne; Schweizer, Michaela; Hüwel, Sabine; Galla, Hans-Joachim; Snaidero, Nicolas; Simons, Mikael; Bückers, Johanna; Low, Philip S; Urlaub, Henning; Gärtner, Jutta; Steinfeld, Robert.
In: NAT COMMUN, Vol. 4, 01.01.2013, p. 2123.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma
AU - Grapp, Marcel
AU - Wrede, Arne
AU - Schweizer, Michaela
AU - Hüwel, Sabine
AU - Galla, Hans-Joachim
AU - Snaidero, Nicolas
AU - Simons, Mikael
AU - Bückers, Johanna
AU - Low, Philip S
AU - Urlaub, Henning
AU - Gärtner, Jutta
AU - Steinfeld, Robert
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Loss of folate receptor-α function is associated with cerebral folate transport deficiency and childhood-onset neurodegeneration. To clarify the mechanism of cerebral folate transport at the blood-cerebrospinal fluid barrier, we investigate the transport of 5-methyltetrahydrofolate in polarized cells. Here we identify folate receptor-α-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptor-α, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells. Both the apical medium of folate receptor-α-transfected rat choroid plexus cells and human cerebrospinal fluid contain folate receptor-α-positive exosomes. Loss of folate receptor-α-expressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-α-mediated folate transport in the cerebrospinal fluid. Intraventricular injections of folate receptor-α-positive and -negative exosomes into mouse brains demonstrate folate receptor-α-dependent delivery of exosomes into the brain parenchyma. Our results unravel a new pathway of folate receptor-α-dependent exosome-mediated folate delivery into the brain parenchyma and opens new avenues for cerebral drug targeting.
AB - Loss of folate receptor-α function is associated with cerebral folate transport deficiency and childhood-onset neurodegeneration. To clarify the mechanism of cerebral folate transport at the blood-cerebrospinal fluid barrier, we investigate the transport of 5-methyltetrahydrofolate in polarized cells. Here we identify folate receptor-α-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptor-α, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells. Both the apical medium of folate receptor-α-transfected rat choroid plexus cells and human cerebrospinal fluid contain folate receptor-α-positive exosomes. Loss of folate receptor-α-expressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-α-mediated folate transport in the cerebrospinal fluid. Intraventricular injections of folate receptor-α-positive and -negative exosomes into mouse brains demonstrate folate receptor-α-dependent delivery of exosomes into the brain parenchyma. Our results unravel a new pathway of folate receptor-α-dependent exosome-mediated folate delivery into the brain parenchyma and opens new avenues for cerebral drug targeting.
KW - Adolescent
KW - Adult
KW - Animals
KW - Cell Polarity
KW - Child
KW - Choroid Plexus
KW - Cytoplasmic Vesicles
KW - Dogs
KW - Exosomes
KW - Female
KW - Folate Receptor 1
KW - Folic Acid
KW - Humans
KW - Madin Darby Canine Kidney Cells
KW - Male
KW - Mice
KW - Models, Biological
KW - Monensin
KW - Protein Transport
KW - Proton-Coupled Folate Transporter
KW - Rats
KW - Tetrahydrofolates
KW - Transcytosis
KW - Transferrin
KW - Young Adult
U2 - 10.1038/ncomms3123
DO - 10.1038/ncomms3123
M3 - SCORING: Journal article
C2 - 23828504
VL - 4
SP - 2123
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
ER -