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Ceruloplasmin Deficiency Reduces Levels of Iron and BDNF in the Cortex and Striatum of Young Mice and Increases Their Vulnerability to Stroke

By Sarah J. Texel, Jian Zhang, Simonetta Camandola, Erica L. Unger, Dennis D. Taub, Raymond C. Koehler, Z. Leah Harris and Mark P. Mattson

Abstract

Ceruloplasmin (Cp) is an essential ferroxidase that plays important roles in cellular iron trafficking. Previous findings suggest that the proper regulation and subcellular localization of iron are very important in brain cell function and viability. Brain iron dyshomeostasis is observed during normal aging, as well as in several neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, coincident with areas more susceptible to insults. Because of their high metabolic demand and electrical excitability, neurons are particularly vulnerable to ischemic injury and death. We therefore set out to look for abnormalities in the brain of young adult mice that lack Cp. We found that iron levels in the striatum and cerebral cortex of these young animals are significantly lower than wild-type (WT) controls. Also mRNA levels of the neurotrophin brain derived neurotrophic factor (BDNF), known for its role in maintenance of cell viability, were decreased in these brain areas. Chelator-mediated depletion of iron in cultured neural cells resulted in reduced BDNF expression by a posttranscriptional mechanism, suggesting a causal link between low brain iron levels and reduced BDNF expression. When the mice were subjected to middle cerebral artery occlusion, a model of focal ischemic stroke, we found increased brain damage in Cp-deficient mice compared to WT controls. Our data indicate that lack of Cp increases neuronal susceptibility to ischemic injury by a mechanism that may involve reduced levels of iron and BDNF

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3174999
Provided by: PubMed Central

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