Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma

被引：262

作者：

Grapp, Marcel ^{[1
]}

Wrede, Arne ^{[2
]}

Schweizer, Michaela ^{[3
]}

Huewel, Sabine ^{[4
]}

Galla, Hans-Joachim ^{[4
]}

Snaidero, Nicolas ^{[5
]}

Simons, Mikael ^{[5
,6
]}

Bueckers, Johanna ^{[7
]}

Low, Philip S. ^{[8
]}

Urlaub, Henning ^{[9
,10
]}

Gaertner, Jutta ^{[1
]}

Steinfeld, Robert ^{[1
]}

机构：

[1] Univ Med Ctr Gottingen, Dept Pediat & Pediat Neurol, D-37075 Gottingen, Germany

[2] Univ Med Ctr Gottingen, Inst Neuropathol, Prion & Dementia Res Unit, D-37075 Gottingen, Germany

[3] Univ Hamburg, Ctr Mol Neurobiol, D-20251 Hamburg, Germany

[4] Univ Munster, Inst Biochem, D-48149 Munster, Germany

[5] Max Planck Inst Expt Med, D-37075 Gottingen, Germany

[6] Univ Med Ctr Gottingen, Dept Neurol, D-37075 Gottingen, Germany

[7] Max Planck Inst Biophys Chem, Dept Nanobiophoton, D-37077 Gottingen, Germany

[8] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA

[9] Max Planck Inst Biophys Chem, Bioanalyt Mass Spectrometry Grp, D-37077 Gottingen, Germany

[10] Univ Med Ctr Gottingen, Dept Clin Chem, D-37075 Gottingen, Germany

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

关键词：

BINDING PROTEIN; INDEPENDENT ENDOCYTOSIS; EPITHELIAL-CELLS; MDCK CELLS; IN-VITRO; TRANSPORT; DEFICIENCY; RECEPTORS; MECHANISM; MICE;

D O I：

10.1038/ncomms3123

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Loss of folate receptor-alpha 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-alpha-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptor-alpha, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells. Both the apical medium of folate receptor-alpha-transfected rat choroid plexus cells and human cerebrospinal fluid contain folate receptor-alpha-positive exosomes. Loss of folate receptor-alpha-expressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-alpha-mediated folate transport in the cerebrospinal fluid. Intraventricular injections of folate receptor-alpha-positive and -negative exosomes into mouse brains demonstrate folate receptor-alpha-dependent delivery of exosomes into the brain parenchyma. Our results unravel a new pathway of folate receptor-alpha-dependent exosome-mediated folate delivery into the brain parenchyma and opens new avenues for cerebral drug targeting.

引用

页数：13

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