Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin?
One of the most striking features of Alzheimer disease (AD) is an accumulation of iron in neurofibrillary tangles and senile plaques. Intriguingly, this iron is found as both iron (II) and iron (III) and is redox-active. To address the issue of whether such iron participates in redox cycling, it was essential to investigate how iron (II) accumulates, since oxidation of iron (II) can lead to the generation of reactive oxygen species. To begin to address this issue, here we investigated ceruloplasmin, a key protein involved in the regulation of the redox state of iron by converting iron (II) to iron (III). Cases of AD and age-matched controls, obtained at autopsy with similar postmortem intervals, display similar levels of ceruloplasmin immunoreactivity that is mainly confined to neurons. However, in marked contrast, cases of AD show a significant increase in ceruloplasmin within the neuropil determined by immunoblot analysis of tissue homogenates as well as a generalized increased neuropil staining. Together, these findings suggest that neuronal induction of ceruloplasmin is feeble in AD, even while there is an increase in tissue ceruloplasmin. Therefore, a failure of neuronal ceruloplasmin to respond to iron may be an important factor that then leads to an accumulation of redox-active iron in neurons in AD.
Castellani
R J
RJ
Department of Pathology, University of Maryland at Baltimore, USA.
Smith
M A
MA
Nunomura
A
A
Harris
P L
PL
Perry
G
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002570:Ceruloplasmin / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism; D019581:Neuropil / Q000378:metabolism; D010084:Oxidation-Reduction
D007501:Iron; D002570:Ceruloplasmin