Fig. 2. Iron metabolism in the brain. Astrocytes express CP to oxidize Fe²⁺.

. Oligodendrocytes, a primary target in inflammatory attack, and synthesize Tf that controls intracellular iron transport. Microglia represent DMT1, APP, and ferritin, assisting neurons to maintain iron hemostasis in the brain environment. They also protect normal neuron function by iron regulation. The ferric iron (Fe³⁺) derived from diet, excreted enterocytes, and reticulocytes binds to transferrin (Tf). This combination uptake in the endothelial surfaces in the BBB is mediated by TfR. Fe³⁺ releases from Tf-TFR complex in the endosome and is catalyzed to ferrous iron (Fe²⁺). Thereby, TfR is recycled to bind to the iron Tf complex in the plasma. Alternatively, Fe²⁺ is transported to cytosol of endothelial cells and extracellular fluid by DMT1 and FPN1, respectively. In addition, released Fe²⁺ is quickly converted to Fe³⁺ by CP, expressed by both astrocytes and endothelial cells followed by bonding to Tf or low molecular weight molecules (e.g., citrate and ATP). Non-Tf-bound iron (NTBI) synthesized in the cytosol is the iron source for oligodendrocytes and astrocytes where Tf is highly saturated by iron^22,23