Ceruloplasmin Regulates Iron Levels in the CNS and Prevents Free Radical Injury
Centre for Research in Neuroscience, The Montreal General Hospital Research Institute and McGill University, Canada

Ceruloplasmin is a ferroxidase that oxidizes toxic ferrous iron to its nontoxic ferric form. We have previously reported that a glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed in the mammalian CNS. To better understand the role of ceruloplasmin in iron homeostasis in the CNS, we generated a ceruloplasmin gene-deficient (Cp/) mouse. Adult Cp mice showed increased iron deposition in several regions of the CNS such as the cerebellum and brainstem. Increased lipid peroxidation was also seen in some CNS regions. Cerebellar cells from neonatal Cp/mice were also more susceptible to oxidative stress in vitro.
Cp/ mice showed deficits in motor coordination that were associated with a loss of brainstem dopaminergic neurons. These results indicate that ceruloplasmin plays an important role in maintaining iron homeostasis in the CNS and in protecting the CNS from ironmediated free radical injury. Therefore, the antioxidant effects of ceruloplasmin could have important implications for various neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease in which iron deposition is known to occur.

“...CONCLUSIONS

Our data indicate that C p is an effective antioxidant in the C NS in vivo and protects neural cells from oxidative stress. The antioxidant f unction of C p is likely to be particularly crucial during CNS injury, such as ischemia or mechanical trauma, when levels of free iron and reactive oxygen species, including H2O2, increase (Hyslop et al., 1995; Palmer et al., 1999). During such injuries, thelevels of C p are also likely to increase because C p is an acute-phase protein. Indeed, levels of C p increase in the retina after optic nerve crush (Levin and Geszvain, 1998).
The pathological changes observed in patients with acerulo-plasminemia and inCp/mice share similarities with otherneurodegenerative diseases. Iron accumulation occurs in the substantia nigra in Parkinson’s disease, in the cortex and amyloidplaques in Alzheimer’s disease, and in the spinal cord in amyo-trophic lateral sclerosis (Gerlach et al., 1994). In addition, levels of free radicals and markers of oxidative injury are also elevatedin these disorders (Olanow, 1993; Boll et al., 1999). Whether areduction in C p levels contributes to the pathology of these
neurodegenerative diseases is not yet known. However, levels of C p are reduced in the cortex in Alzheimer’s disease (Connor etal., 1993), and the ferroxidase activity of C p is reduced in the cerebrospinalfluid in Parkinson’s disease (Boll et al., 1999). It is therefore possible that a reduction in C p may contribute to the neurodegenerativeprocess in these disorders by leading to an increase in the levels of ferrous iron, which can promote the generation of toxic free radicals. Thus, in addition to providing insights into the human disease aceruloplasminemia, Cp/mice could also serve as a usef ul model to study the role of Cp in the more common neurodegenerative diseases. Furthermore, these mice could potentially be used to test novel therapeutic strategies
to prevent iron-mediated free radical injury in the CNS....”

full paper: http://www.jneurosci.org/content/22/15/6578.full.pdf