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.