Age-related changes in iron homeostasis and cell death in the cerebellum of ceruloplasmin-deficient mice

Young Jeong Suh, Samuel David

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

Iron is essential for a variety of cellular functions, but its levels and bioavailability must be tightly regulated because of its toxic redox activity. A numberof transporters, binding proteins, reductases, and ferroxidases help maintain iron homeostasis to prevent cell damage. The multi-copper ferroxidase ceruloplasmin (Cp) converts toxic ferrous iron to its nontoxic ferric form and is required for iron efflux from cells. Absence of this enzyme in humans leads to iron accumulation and neurodegeneration in the CNS. Here we report on the changes that occur in the cerebellum of Cp null (Cp-/-) mice with aging. We show that iron accumulation, which is reflected in increased ferritin expression, occurs mainly in astrocytes by 24 months in Cp-/- mice and is accompanied by a significant loss of these cells. In contrast, Purkinje neurons and the large neurons in the deep nuclei of Cp-/- mice do not accumulate iron but express high levels of the iron importer divalent metal transporter 1, suggesting that these cells may be iron deprived. This is also accompanied by a significant reduction in the number of Purkinje neurons. These data suggest that astrocytes play a central role in the acquisition of iron from the circulation and that two different mechanisms underlie the loss of astrocytes and neurons in Cp-/- mice. These findings provide a better understanding of the degenerative changes seen in humans with aceruloplasminemia and have implications for normal aging and neurodegenerative diseases in which iron accumulation occurs.

Original languageEnglish (US)
Pages (from-to)9810-9819
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number38
DOIs
StatePublished - Sep 20 2006
Externally publishedYes

Keywords

  • Aging
  • Astrocytes
  • Blood-brain
  • Cerebellum
  • Neuron death
  • Neuropathology

ASJC Scopus subject areas

  • Neuroscience(all)

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