Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

Figure 1

Iron metabolism in the brain. Transferrin (Tf) bound to ferric iron (Fe³⁺) is taken up by the Tf receptor (TfR) in the luminal membrane of endothelial cells, and Fe³⁺-laden Tf and TfR complex are internalized into endosomes. Fe³⁺-bound Tf is reduced by duodenal cytochrome b to ferrous iron (Fe²⁺). Fe²⁺ may be transported to the cytosol by the divalent metal transporter l (DMT1) in the endosomal membrane and exported into the extracellular fluid by ferroportin l (FPN1). FPN1 interacts with the amyloid precursor protein (APP), which may function as a ferroxidase at the plasma membrane of neurons, microglia, and astrocytes. After Fe²⁺ release, Tf is recycled to bind to Fe³⁺ in the blood. Ceruloplasmin (CP) on the membrane of astrocytes oxidizes Fe²⁺ to Fe³⁺ to bind for subsequent binding to Tf. Neurons take up Tf-bound and non-Tf-bound iron (NTBI). NTBI may also bind to citrate and ATP derived from astrocytes to function as a source of iron for oligodendrocytes and astrocytes. Oligodendrocytes synthesize Tf, which play a role in intracellular transport. The cytosolic iron storage protein ferritin traps and stores NTBI in the brain cells.