Iron Regulatory Protein 2 is Involved in Brain Copper Homeostasis

Abstract

Trace metal homeostasis is tightly controlled in the brain, as even a slight dysregulation may severely impact normal brain function. This is especially apparent in Alzheimer's disease, where brain homeostasis of trace metals such as copper and iron is dysregulated. As it is known that iron and copper metabolism are linked, we wanted to investigate if a common mechanism could explain the increase in iron and decrease in copper seen in Alzheimer's disease brain. Amyloid-beta protein precursor (AbetaPP) has been implicated in copper efflux from the brain. Furthermore, it was shown that iron regulatory proteins (IRP), which regulate iron homeostasis, can block AbetaPP mRNA translation. In a correlative study we have therefore compared brain regional copper levels and AbetaPP expression in mice with a targeted deletion of IRP2-/-. Compared with controls, six week old IRP2-/- mice had significantly less brain copper in the parietal cortex, hippocampus, ventral striatum, thalamus, hypothalamus, and whole brain, while AbetaPP was significantly upregulated in the hippocampus (p < 0.05) and showed a trend toward upregulation in the thalamus (p < 0.1). This is the first study to demonstrate that iron regulatory proteins affect brain copper levels, which has significant implications for neurodegenerative diseases.