Fig. 2.

Entrance of iron into the brain: Holo-Tf binds to TfR on the membrane of the capillary endothelial cells of the BBB and choroid plexus epithelial cells of the BCB. The reduced form of iron can export from the membrane by ferroportin toward interstitial fluid and cerebrospinal fluid after dissociation from TfR. After re-oxidizing of Fe²⁺ to Fe³⁺ mediated by ferroxidases, Fe³⁺ binds to transferrin. Holo-Tf and free iron ions can freely exchange between CSF and ISF. There are ependymal cells between these two fluid compartments that are linked by gap junctions. Neural cells (e.g. oligodendrocytes, astrocytes, microglia, and neurons) uptake Holo-Tf via receptor-mediated endocytosis in ISF. There are several mechanisms for iron recycle to the systemic circulation. For example, Holo-Tf binding to TfR on the abluminal membrane of BBB and iron reabsorption into the blood plasma which is triggered from subarachnoid and transporting through BCB. However, the exact mechanism of iron export back to the systemic circulation is not clear. Holo-Tf, Holo-transferrin; TfR, transferrin receptor; Apo-Tf, apo-transferrin; DMT1, Divalent metal transporter 1; NTBI, non-transferrin bound iron; BBB, blood–brain barrier; BCB, blood-CSF barrier; CSF, cerebrospinal fluid; ISF, interstitial fluid; CME, clathrin-mediated endocytosis. This Figure was created by BioRender (https://biorender.com/)