Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mis-metabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders. Antioxid. Redox Signal. 20, 1324–1363.

Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of AD include extracellular accumulation of amyloid β (Aβ) and intracellular deposits of hyper-phosphorylated tau (p-tau). Neuroinflammation and brain iron dyshomeostasis accompany Aβ and p-tau deposits and, together, lead to progressive neuronal death and dementia. The accumulation of Aβ and iron in drusen, the hallmark of AMD, and Aβ and p-tau in retinal ganglion cells (RGC), the main retinal cell type implicated in glaucoma, and accompanying inflammation suggest overlapping pathology. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline. Some are caused by degeneration of the visual cortex, while others are due to RGC loss or AMD-associated retinal degeneration. Here, we review recent information on Aβ, p-tau, chronic inflammation, and iron dyshomeostasis as common pathogenic mechanisms linking the three degenerative conditions, and iron chelation as a common therapeutic option for these disorders. Additionally discussed is the role of prion protein, infamous for prion disorders, in Aβ-mediated toxicity and, paradoxically, in neuroprotection.

Despite overwhelming evidence implicating the prion protein (PrP) in prion disease pathogenesis, the normal function of this cell surface glycoprotein remains unclear. In previous reports we demonstrated that PrP mediates cellular iron uptake and transport, and aggregation of PrP to the disease causing PrP-scrapie (PrP^Sc) form results in imbalance of iron homeostasis in prion disease affected human and animal brains. Here, we show that selective deletion of PrP in transgenic mice (PrP^KO) alters systemic iron homeostasis as reflected in hematological parameters and levels of total iron and iron regulatory proteins in the plasma, liver, spleen, and brain of PrP^KO mice relative to matched wild type controls. Introduction of radiolabeled iron (⁵⁹FeCl₃) to Wt and PrP^KO mice by gastric gavage reveals inefficient transport of ⁵⁹Fe from the duodenum to the blood stream, an early abortive spike of erythropoiesis in the long bones and spleen, and eventual decreased ⁵⁹Fe content in red blood cells and all major organs of PrP^KO mice relative to Wt controls. The iron deficient phenotype of PrP^KO mice is reversed by expressing Wt PrP in the PrP^KO background, demonstrating a functional role for PrP in iron uptake and transport. Since iron is required for essential metabolic processes and is also potentially toxic if mismanaged, these results suggest that loss of normal function of PrP due to aggregation to the PrP^Sc form induces imbalance of brain iron homeostasis, resulting in disease associated neurotoxicity.

Prion protein (PrPC ) is implicated in the pathogenesis of prion disorders, but its normal function is unclear. We demonstrate that PrPC is a ferrireductase (FR), and its absence causes systemic iron deficiency in PrP knock-out mice (PrP-/- ). When e

Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrP^Sc), a β-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrP^C). Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s) leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease–affected human, hamster, and mouse brains show increased total and redox-active Fe (II) iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD)–affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels, implicating PrP^Sc as the underlying cause of iron deficiency. Increased binding of Tf to the cerebellar Purkinje cell neurons of sCJD brains further indicates upregulation of TfR and a phenotype of neuronal iron deficiency in diseased brains despite increased iron levels. The likely cause of this phenotype is sequestration of iron in brain ferritin that becomes detergent-insoluble in PrP^Sc-infected cell lines and sCJD brain homogenates. These results suggest that sequestration of iron in PrP^Sc–ferritin complexes induces a state of iron bio-insufficiency in prion disease–affected brains, resulting in increased uptake and a state of iron dyshomeostasis. An additional unexpected observation is the resistance of Tf to digestion by proteinase-K, providing a reliable marker for iron levels in postmortem human brains. These data implicate redox-iron in prion disease–associated neurotoxicity, a novel observation with significant implications for prion disease pathogenesis. Prion disorders are neurodegenerative conditions of humans and animals that are invariably fatal. The main agent responsible for neurotoxicity in all prion disorders is PrP-scrapie (PrP^Sc), a β-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrP^C). Deposits of PrP^Sc in the brain parenchyma are believed to induce neurotoxicity, though the underlying mechanisms are not entirely clear. Emerging evidence from prion-infected cell and mouse models implicates redox-iron in prion disease–associated neurotoxicity. However, a systematic evaluation of iron homeostasis in prion disease–affected brains and the underlying mechanism of iron dyshomeostasis are lacking. In this report, we demonstrate that prion disease–affected human, mouse, and hamster brains exhibit a state of iron deficiency in the presence of excess total brain iron, resulting in a state of iron imbalance. The underlying cause of this phenotype is likely sequestration of iron in cellular ferritin that becomes detergent-insoluble, possibly due to association with PrP^Sc. This results in a state of iron bio-insufficiency, leading to increased iron uptake by the cells and worsening of the state of iron imbalance. Since iron is highly toxic if mismanaged, these results implicate iron imbalance as a significant contributing factor in prion disease–associated neurotoxicity.