The Significance of the Choroid Plexus for Cerebral Iron Homeostasis

The homeostasis of the brain interstitial fluid is sustained by two brain barriers, i.e. the blood-brain barrier (BBB) formed by brain capillary endothelial cells and the blood-cerebrospinal fluid (CSF) barrier, which both selectively allow transport of nutrients and metals into the brain. Iron is essential for normal brain function but detrimental in excess, hence justifying a tightly regulated cerebral iron homeostasis based on the transport of iron from the periphery across the brain barriers. Regulation of iron uptake involves proteins like transferrin receptor, divalent metal transporter 1 (DMT1), ferritin and ferroportin. It is commonly accepted that iron uptake and transport across the blood-CSF barrier are mediated by the transferrin receptor although by two principally different mechanisms. Transferrin complexed with iron can engage with the transferrin receptor and traverse the choroid plexus epithelial cells by receptor-mediated transcytosis. Moreover, Fe3+ can detach from transferrin within slightly acidic endosomes, escape into the cytosol by DMT1-mediated pumping after Fe3+ has been reduced to Fe2+. In the cytosol, iron is either stored in ferritin or exported into the CSF mediated by ferroportin. Within the CSF, iron binds to transferrin primarily synthesized or secreted by the choroid plexus. Non-transferrin-bound iron (NTBI) is present in the CSF, favoring the argument that the iron-binding capacity of transferrin is exceeded in CSF. We hypothesize that transferrin derived from the CSF play a crucial role for binding of iron transported through the BBB, and for further transport of iron within the brain interstitium and subsequent delivery to transferrin receptor-expressing neurons.