Metal Dyshomeostasis and Inflammation in Alzheimer’s and Parkinson’s Diseases: Possible Impact of Environmental Exposures
Figure 1
Putative linkage between cytokine (IL-6) and iron (Fe) induced hepcidin production with APP-mediated copper (Cu) lowering in the AD brain. Both liver and brain cells can produce the iron regulatory peptide hepcidin which may cross the blood-brain barrier (BBB). (A) In neurons, plasma membrane localized ferroportin exports ferrous iron (Fe2+) which is oxidized extracellularly by means of the ferroportin-collaborating amyloid precursor protein (APP) which has ferroxidase activity [18] and which loads ferric iron (Fe3+) into transferrin. (B) Hepcidin binding to ferroportin causes its internalization and lysosomal breakdown, preventing iron export [19, 20]. In response, iron levels in individual neurons may increase during aging, initiating APP-mRNA iron responsive constitutive translation of APP [21] which contains a copper binding domain. (C) APP travels to the plasma membrane and is cleaved by secretases to form short peptides, of which the Aβ peptide can form plaques containing metal ions [22–24]. Lowered neuronal copper levels, for which the cellular pool is low, can affect vital copper enzymes negatively (e.g., mitochondrial respiratory ATP producing COX, Cu/Zn-SOD, etc.). Aβ-plaque attacking microglia release various cytokines including IL-6 and ROS, that along with ROS generated from Aβ-plaque associated redox-cycling metals (e.g., Fe and Cu ions) inflict free radical damage to neurons. Liver hepcidin production affects iron metabolism in several organs (see text).
