Brain iron acquisition: An overview of homeostatic regulation and disease dysregulation

Brain iron homeostasis is crucial for neurological health, with pathological fluctuations in brain iron levels associated with a variety of neurological disorders. Low levels are connected to cognitive impairment and restless legs syndrome, while high levels are connected to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Given the detrimental effects unrestricted iron can have, regulated entry into the brain via transferrin and H‐ferritin is critical. Endothelial cells of the blood–brain barrier are the site of iron transport regulation. The movement of iron through endothelial cells into the brain can be divided into three distinct processes: uptake, transcytosis, and release. Each process possesses external and internal influences on the regulation at each stage. This review discusses the mechanisms of iron uptake, transcytosis, and release at the blood–brain barrier, as well as the elements that contribute to regulation. Additionally, we explore the dysregulation of brain iron in Alzheimer's disease, Parkinson's disease, and restless legs syndrome. Acquisition of brain iron can be divided into three processes: uptake, transcytosis, and release. Uptake occurs when iron bound to transferrin (holo‐Tf) and/or H‐ferritin is internalized through the transferrin receptor (TfR) and Tim‐1, respectively. Holo‐Tf can be trancytosed, but most of the iron is released in the endosome generating iron‐free Tf (apo‐Tf) recycled to the blood. Iron is released from the endosome and exported to the brain through ferroportin (Fpn). The mechanism for H‐ferritin iron delivery is currently under investigation. Here, we review how brain iron acquisition is regulated or dysregulated in Alzheimer's disease, Parkinson's disease, and restless legs syndrome.