title: Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma.
abstract: 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.
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Grapp
authors.forename: Arne
authors.initials: A
authors.lastname: Wrede
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Sabine
authors.initials: S
authors.lastname: Hüwel
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Galla
authors.forename: Nicolas
authors.initials: N
authors.lastname: Snaidero
authors.forename: Mikael
authors.initials: M
authors.lastname: Simons
authors.forename: Johanna
authors.initials: J
authors.lastname: Bückers
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
authors.forename: Robert
authors.initials: R
authors.lastname: Steinfeld
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016764:Cell Polarity / Q000187:drug effects; D002648:Child; D002831:Choroid Plexus / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D058975:Folate Receptor 1 / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008954:Models, Biological; D008985:Monensin / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D058979:Proton-Coupled Folate Transporter / Q000378:metabolism; D051381:Rats; D013763:Tetrahydrofolates / Q000378:metabolism; D057900:Transcytosis / Q000187:drug effects; D014168:Transferrin / Q000494:pharmacology; D055815:Young Adult
chemical_list: D058975:Folate Receptor 1; D058979:Proton-Coupled Folate Transporter; C505058:SLC46A1 protein, human; D013763:Tetrahydrofolates; D014168:Transferrin; D008985:Monensin; D005492:Folic Acid; C005984:5-methyltetrahydrofolate