Dysregulation of iron metabolism in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis

Abstract

Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs). Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD) and Parkinson's disease (PD), circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS). Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs.

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.