Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

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 number of 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 Ϫ/Ϫ ) mice with aging. We show that iron accumulation, which is reflected in increased ferritin expression, occurs mainly in astrocytes by 24 months in Cp Ϫ/Ϫ 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 Ϫ/Ϫ 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 Ϫ/Ϫ 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.

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

“…Interestingly, patients deficient in ceruloplasmin have increased brain iron and neurological symptoms including parkinsonism (45). Importantly, iron accumulates in astrocytes in this disease and, at least early, neurons may be iron-starved, similar to ceruloplasmin-deficient mice (46). This observation suggests that sequestered iron is not available to neurons, even though it is increased locally.…”

Dysregulation of Iron Homeostasis in the CNS Contributes to Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Total RNA was purified from cervical, thoracic, and lumbar segments of the spinal cord using the RNeasy Lipid Tissue kit (QIAGEN), and quantitative real-time reverse transcription (QRT)-PCR was performed using the Brilliant Probebased QRT-PCR reagents and MX4000 (Stratagene), both following the protocols of the manufacturer. Gene-specific primers and Taqman probes were used as previously described (Jeong and David, 2006). QRT-PCR for peptidylprolyl isomerase A (PPIA) was performed for use as an internal control (Feroze-Merzoug et al, 2002).…”

“…SOD1 G37R and control mice were deeply anesthetized as above and perfused with 0.1 M phosphate buffer, followed by 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.2, and 14 m cryostat sections were obtained. Double immunofluorescence labeling of tissue sections was performed as described previously (Jeong and David, 2006). Briefly, the tissue sections were incubated with PBS containing 2% normal goat serum and 1% ovalbumin to block nonspecific binding of antibodies.…”

An inhibition of ceruloplasmin expression induced by cerebral ischemia in the cortex and hippocampus of rats

“…Ceruloplasmin (Cp) is a ferroxidase that can safely convert toxic ferrous (Fe 2+ ) iron to nontoxic ferric (Fe 3+ ) form [1] . A secreted form of Cp is expressed mainly by liver, and a glycosylphosphatidylinositol (GPI)-anchored form is expressed by astrocytes in the central nervous system(CNS) [2,3] .…”