Brain iron homeostasis and neurodegenerative disease

Abstract

AD= : Alzheimer disease; APP= : amyloid precursor protein; ATP= : adenosine triphosphate; BBB= : blood–brain barrier; DMT1= : divalent metal transporter-1; FA= : Friedreich ataxia; FTL= : ferritin light chain; FTH= : ferritin heavy chain; NBIA= : neurodegeneration with brain iron accumulation; NTBI= : non–transferrin-bound iron; PANK2= : pantothenate kinase 2; PD= : Parkinson disease; PKAN= : pantothenate kinase–associated neurodegeneration; TfR1= : transferrin receptor 1. Iron is essential for multiple functions in the CNS, including DNA synthesis, gene expression, myelination, neurotransmission, and mitochondrial electron transport. Several proteins implicated in brain iron homeostasis are involved in disorders associated with abnormal iron metabolism. A basic understanding of mechanisms of iron homeostasis is of clinical relevance, as either accumulation or depletion of intracellular iron may impair normal function and promote cell death. Iron accumulates in selective brain regions during aging, in acquired neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD), and in genetic disorders such as neurodegeneration with brain iron accumulation (NBIA). Dysregulation of iron homeostasis is also a critical feature of Friedreich ataxia (FA). The link between iron and neurodegenerative disease provides potential therapeutic targets for these disorders. Brain iron metabolism and its implications in neurodegeneration have been the subjects of excellent reviews.1–6 Some general concepts, unresolved issues, and clinical correlations are briefly discussed here. The CNS is separated from the systemic circulation by the blood–brain barrier (BBB), a tight epithelial barrier analogous to that of the mammalian duodenum, which is the site of absorption of dietary iron. After absorption, iron in its oxidized (ferric) form binds to serum transferrin and is distributed throughout the general circulation. The presence of a BBB explains the relative independence of the brain iron from the total body iron content. This is reflected by the absence of brain iron overload in mouse models and in humans with hemochromatosis due to mutations of the HFE gene, encoding a protein that regulates iron absorption.1,2 ### Incorporation and transport of iron in the nervous system. Iron incorporation and transport in the brain depends on interactions between the endothelial cells and astrocytes (figure). Brain endothelial cells express the transferrin receptor 1 (TfR1) in their luminal membrane; this receptor binds iron-loaded transferrin and internalizes this complex in endosomes. Within the endosomes, …