Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma

Nat Commun. 2013:4:2123. doi: 10.1038/ncomms3123.

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.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Cell Polarity / drug effects
  • Child
  • Choroid Plexus / cytology*
  • Choroid Plexus / metabolism*
  • Choroid Plexus / ultrastructure
  • Cytoplasmic Vesicles / drug effects
  • Cytoplasmic Vesicles / metabolism
  • Dogs
  • Exosomes / drug effects
  • Exosomes / metabolism*
  • Exosomes / ultrastructure
  • Female
  • Folate Receptor 1 / metabolism
  • Folic Acid / metabolism*
  • Humans
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Models, Biological
  • Monensin / pharmacology
  • Protein Transport / drug effects
  • Proton-Coupled Folate Transporter / metabolism
  • Rats
  • Tetrahydrofolates / metabolism
  • Transcytosis* / drug effects
  • Transferrin / pharmacology
  • Young Adult

Substances

  • Folate Receptor 1
  • Proton-Coupled Folate Transporter
  • SLC46A1 protein, human
  • Tetrahydrofolates
  • Transferrin
  • Monensin
  • Folic Acid
  • 5-methyltetrahydrofolate