Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma

Marcel Grapp, Arne Wrede, Michaela Schweizer, Sabine Hüwel, Hans-Joachim Galla, Nicolas Snaidero, Mikael Simons, Johanna Bückers, Philip S. Low, Henning Urlaub, Jutta Gärtner and Robert Steinfeld ()
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Marcel Grapp: University Medical Center Göttingen
Arne Wrede: Prion and Dementia Research Unit, Institute of Neuropathology, University Medical Center Göttingen
Michaela Schweizer: Centre for Molecular Neurobiology, University of Hamburg
Sabine Hüwel: Institute of Biochemistry, University of Münster
Hans-Joachim Galla: Institute of Biochemistry, University of Münster
Nicolas Snaidero: Max-Planck-Institute of Experimental Medicine
Mikael Simons: Max-Planck-Institute of Experimental Medicine
Johanna Bückers: Max-Planck-Institute for Biophysical Chemistry
Philip S. Low: Purdue University
Henning Urlaub: The Bioanalytical Mass Spectrometry Group, Max-Planck-Institute for Biophysical Chemistry
Jutta Gärtner: University Medical Center Göttingen
Robert Steinfeld: University Medical Center Göttingen

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3123

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