Iron overload and antioxidative role of perivascular astrocytes in aceruloplasminemia

Abstract

Aceruloplasminemia (ACP) is an inherited disorder of iron metabolism caused by the lack of ceruloplasmin activity; the neuropathological hallmarks are excessive iron deposition, neuronal loss, bizarrely deformed astrocytes, and numerous 'grumose or foamy spheroid bodies (GFSBs)'. We histopathologically examined two autopsied ACP brains, and observed for the first time that GFSBs form in clusters at the ends of perivascular astrocytic foot processes. Both the deformed astrocytes and the GFSBs contained ferric iron and were intensely immunolabelled with antibodies against the antioxidant proteins ferritin and manganese superoxide dismutase (Mn SOD). Ceruloplasmin is largely produced by perivascular astrocytes in the central nervous system and exhibits a ferroxidase activity that inhibits iron-associated lipid peroxidation and hydroxyl radical formation; therefore, the lack of ceruloplasmin causes direct oxidative stress on astrocytes. The intense immunolabelling of ferritin and Mn SOD most likely reflects a defensive response to iron-mediated oxidative stress. This study suggests that astrocytes play key roles in iron trafficking and the detoxification of iron-mediated free radicals at the blood-brain barrier and in the parenchyma in ACP brain. The antioxidative ability of astrocytes is one of their essential neuroprotective effects, and the decompensation of this ability may lead to secondary neuronal cell death in ACP.

Cellular and subcellular localizations of nonheme ferric and ferrous iron in the rat brain: a light and electron microscopic study by the perfusion-Perls and -Turnbull methods

“…These astrocytes probably sequestrate iron to protect myelinated nerve fibers against oxidative stress, in addition to the regulation of iron uptake and transport into the parenchyma. Astrocytes are the major source of ceruloplasmin, a ferroxidase which effectively inhibits Fe(II)-mediated OH formation and lipid peroxidation (Vassiliev et al, 2005;Oide et al, 2006).…”

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

“…The profound cortical involvement has not been reported in other NBIAs and probably underlie the high prevalence of cognitive dysfunction. Autopsy findings include mild degree of cortical atrophy, large iron deposits in basal ganglia, thalami, dentate nuclei and cerebral cortices predominantly in the perivascular spaces localized mostly to terminal astrocytic processes and deformed astrocytes with swollen, oxidatively damaged astrocytic foot processes appearing as globular structures [151][152][153]. These results suggest that astrocytes, which are necessary for brain iron uptake, detoxification and further trafficking, bear the brunt of the disease.…”

“…Decreased activity of mitochondrial respiratory chain complexes I and IV and elevated markers of lipid peroxidation were also described in autopsied brains [154]. Overall, there is good evidence that enhanced oxidative stress caused by redox active iron is a major cause of neurodegeneration in aceruloplasminemia [152,153,155]. Neuronal cell death may be partially secondary to the loss of protective function normally provided by astrocytes.…”

Superficial siderosis associated with aceruloplasminemia. Case report

“…Several neuropathological studies on ACP have shown that iron accumulation is mainly found in astrocytes around the blood vessels in the brain parenchyma [7][8][9]; however, little attention has been paid to iron accumulation around leptomeningeal or periventricular regions in ACP. The present case prompted us to examine this neuroradiologically and neuropathologically.…”

“…In the brain, Cp is expressed mainly in astrocytes, ependymal cells, and pia mater cells [5,6]. At the cellular level, iron mainly accumulates in astrocytes in the basal ganglia, thalamus, and dentate nucleus in the cerebellum [7][8][9].…”