Regulation of copper homeostasis by the brain barriers: Effects of iron overload and iron deficiency

Andrew D Monnot, Purdue University

Abstract

Copper (Cu) and iron (Fe) are essential for brain development and metabolism. Abnormal homeostasis of these two metals has been implicated in the pathogenesis of various neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Wilson's disease. Despite its critical role in brain physiology, knowledge on Cu transport, distribution, homeostatic regulation, and the impact of Fe status remains largely unclear. The studies presented in this dissertation were designed to investigate the regulation of Cu transport and Cu transport proteins by Fe status at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB), as well as the distribution of Cu in the brain. Iron deficiency (FeD) and iron overload (FeO) treatments resulted in a significant increase (+55%) and decrease (-56%) in CSF Cu levels (p<0.05), respectively; however, neither treatment had any effect on CSF Fe levels. ICP-MS analysis revealed that while serum Cu was linearly associated with CSF Cu (r=0.792, p<0.01), there was no association between CSF and serum Fe. Serum Cu levels were inversely associated with those of Fe (r=0.754, p<0.01); yet no association between Cu and Fe was observed in the CSF. The FeD, but not FeO, led to significant increases in Cu levels in brain parenchyma and the choroid plexus. In situ brain perfusion studies demonstrated that the rate of Cu transport into the brain parenchyma and capillaries was significantly faster in FeD rats (+92%). In addition, Cu clearance in FeD animals was greater than in control animals as demonstrated by ventriculo-cisternal brain perfusion, suggesting an increased Cu uptake from the CSF by the choroid plexus. The results of mRNA expression indicate that FeD is responsible for the upregulation of DMT1, but not Ctr1 at the BCB, likely contributing to the enhanced Cu uptake found at the barriers. The X-ray fluorescence imaging studies demonstrated an abundant Cu accumulation in the subventricular zone (SVZ) of the lateral ventricles. Taken together these results suggest that (i) Cu enters the central nervous system via the BBB and exits via the BCB and that (ii) DMT1 regulation at the brain barriers contributes mainly to Cu accumulation in the brain following FeD treatment.

Degree

Ph.D.

Advisors

Zheng, Purdue University.

Subject Area

Neurosciences|Toxicology|Surgery

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