Address for correspondence: Torben Moos, Department of Medical Anatomy, Section B, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark. Voice: +45-35327264; fax: +45-35327252. t.moos{at}mai.ku.dk
Ann N.Y. Acad. Sci. 1012: 14-26 (2004).
Neurons need iron, which is reflected in their expression of
the transferrin receptor. The concurrent expression of the ferrous
iron transporter, divalent metal transporter I (DMT1), in neurons
suggests that the internalization of transferrin is followed
by detachment of iron within recycling endosomes and transport
into the cytosol via DMT1. To enable DMT1-mediated export of
iron from the endosome to the cytosol, ferric iron must be reduced
to its ferrous form, which could be mediated by a ferric reductase.
The presence of nontransferrin-bound iron in brain extracellular
fluids suggests that neurons can also take up iron in a transferrin-free
form. Neurons are thought to be devoid of ferritin in many brain
regions in which there is an association between iron accumulation
and cellular damage, for example, neurons of the substantia
nigra pars compacta. The general lack of ferritin together with
the prevailing expression of the transferrin receptor indicates
that iron acquired by activity of transferrin receptors is directed
toward immediate use in relevant metabolic processes, is exported,
or is incorporated into complexes other than ferritin. Iron
has long been considered to play a significant role in exacerbating
degradation processes in brain tissue subjected to acute damage
and neurodegenerative disorders. In brain ischemia, the damaging
role of iron may depend on the inhibition of detoxifying enzymes
responsible for catalyzing the oxidation of ferrous iron. Brain
ischemia may also lead to an increase in iron supply to neurons
as transferrin receptor expression by brain capillary endothelial
cells is increased. Pharmacological blockage of the transferrin
receptor/DMT1-mediated uptake could be a target to prevent further
iron uptake. In chronic neurodegenerative settings, a deleterious
role of iron is suggested since cases of Alzheimer's disease,
Parkinson's disease, and Huntington's disease have a significantly
higher accumulation of iron in affected regions. Dopaminergic
neurons are rich in neuromelanin, shown to be more redox-active
in Parkinson's disease cases. Iron-containing inflammatory cells
may, however, account for the main portion of iron present in
neurodegenerative disorders. More knowledge about iron metabolism
in normal and diseased neurons is warranted as this may identify
pharmaceutical targets to improve neuronal iron management.
