Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma

Abstract

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

Decreased Amyloid-β Pathologies by Intracerebral Loading of Glycosphingolipid-enriched Exosomes in Alzheimer Model Mice

“…The exosome solution (2 mg of protein/ml) contained 2.67 ϫ 10 12 particles/ml, which is ϳ35 times higher than the concentration of the exosomes in mouse CSF (7.51 ϫ 10 10 particles/ml). The intraventricularly injected exosomes have been reported to penetrate into brain parenchyma (15). After 2 weeks, there was an approximate 50% reduction in total A␤ and A␤ 1-42 levels and 35% reduction in A␤ 1-38 levels in the hippocampus of the exosome-treated APP mice compared with those infused with vehicle ( Fig.…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Factors in the blood are also transported across the BCSFB. One example is folate, which is transcytosed and released in exosomes into the CSF to reach the brain parenchyma [55]. This choroidal In addition to being a source of factors via transport and synthesis, the choroid plexus is a sensor of different states.…”

“…These factors can reach distal areas of the brain via bulk flow of the CSF and can act in both an autocrine and paracrine manner [63,137]. In addition to diffusible factors, exosomes containing signaling factors and non-coding (nc) RNAs, such as long ncRNAs and miRNAs, are present in the CSF [11] and can be choroid plexus-derived [6,55]. Finally, the choroid plexuses also contain a large array of enzymes and act as an enzymatic or metabolic barrier, by modulating the activity and availability of neurotransmitters, peptides, growth factors, hormones, drugs and xenobiotics.…”

When the brain tells the blood how to clot

“…In fact, other studies suggested that vesicles, biological or synthetic, in blood might invade the brain. 8,9 What is novel and counterintuitive in this present study is that this process might not be unidirectional. Thus, assuming that the mechanism of action of brain-derived microparticles, unveiled in this study, also occurs in humans with trauma brain injury, the authors suggest that the neutralization of the key actor phosphatidylserine, by annexin V or lactadherin, for instance, may have therapeutic value.…”