Figure 1.
Plasma Tf-iron is taken up by the Tf/TfR pathway, and NTBI by the metal transporters DMT1, Zip8, or Zip14 on the apical plasma membrane of capillary endothelial cells and transported across the basolateral membrane to brain interstitial fluid and CSF by the coupled action of Fpn and the ferroxidase ceruloplasmin (Cp) secreted by astrocytes. Cp oxidizes Fe2+ to Fe3+ that binds CSF Tf or circulates as NTBI. Astrocytes lack TfR and utilize NTBI that requires reduction to Fe2+ by FR proteins dcytb, steap3, or PrPC before uptake by metal transporters. Microglia store iron released from phagocytosed cells and excess NTBI in the extracellular milieu in ferritin. Neurons take up Tf-iron by the Tf/TfR pathway, and NTBI through metal transporters as in astrocytes. Oligodendrocytes synthesize and utilize Tf-iron and also take up ferritin iron by the Tim-2 receptor. Internalized iron contributes to the cytosolic labile iron pool for metabolic purposes and excess is oxidized and stored in ferritin. Most cells express Fpn, and export excess Fe2+ through the coupled action of Fpn and Cp. Cp: ceruloplasmin; DMT1: divalent metal transporter 1; F: ferritin; Fpn: ferroportin; FR: ferrireductase; NTBI: non-transferrin bound iron; Tf: transferrin; TfR: transferrin receptor.
Figure 2.
Hypothetical model of brain iron dyshomeostasis in neurodegenerative disorders.
Primary triggers of neurotoxicity include dysfunction or aggregation of the protein implicated in the pathogenesis of a specific neurodegenerative condition and other less defined factors including aging. Microglia and astrocytes respond to neuronal death and mount a protective response, which is soon overwhelmed by the accumulation of redox-active protein aggregates that induce neurotoxicity and accumulation of additional protein aggregates, increase in brain iron dyshomeostasis, and oxidative stress. These responses are inter-linked, and form a vicious cycle. Inflammatory response to neuronal death increases cytokine release that activates astrocytes and increases microglial activity and death with the release of intracellular iron. These events increase iron imbalance, redox-iron mediated protein aggregation, and significantly increase neurotoxicity. Brain iron dyshomeostasis occurs early and is one of the primary triggers of neurotoxicity if the pathogenic protein is involved in cellular iron metabolism. In other cases, iron dyshomeostasis is initiated by neuronal death, is fueled by microgliosis, activated astrocytes, and redox-active protein aggregates, and spirals when inflammation sets in, amplifying the neurotoxicity.