concentrations of brain iron revealed in this manner were 200 mg/g wet
weight, notably in regions such as the globus pallidus, red nucleus, substantia
nigra, and putamen. An extensive review of iron, ferritin, and transferrin
concentrations by region is tabula ted elsewhere [12], and perhaps the most
striking difference be tween findings with biochemical assay and histochemical
staining is for the white matter, where concentrations of iron are typically
equivalent to those in the gray, and in specific regions such as the motor cortex
can exceed those in adjacent gray matter [69, 70]. In the healthy brain, the
extrapyramidal regions (associated with motor function) exhibi t the highest
concentrations of iron, although these high concentrations are not present at
birth and tend to accumulate on approaching adulthood. The role of these high
concentrations is not understood, as known processes utilizing brain iron only
require 510 % of that actually present [10]. In general, ferritin distribution
closely matches iron distribution, with concentrations in the basal ganglia
being two to three times those in the cerebral cortex. Ferritin levels in the
cortical gray and adjacent white matter are also similar [12, 69].
At the cellular level, Perls staining originally demonstrated iron in microglia,
oligodendrocytes, astrocytes, nerve cells, and possibly in axons and myelin
sheaths [67]. Oligodendrocytes stain most intensely for iron in the human brain,
although they exhibit patchy staining in white matter, and the significance of
this is not known [18]. Expression of ferritin occurs in oligodendrocytes,
neurons, and microglia, which suggests that all these cells have iron storage
capacity [10]. Differences in the ferritin isoforms occur at the cellular as well as
the regional level. Neurons are rich in H-chain ferritin, favoring high iron
uptake and exhibiting peroxidase activity, while macrophages and microglia
express primarily L-chain ferritin and are associated with iron storage [70].
Oligodendrocytes exhibit a mixture of H- and L-chain ferritin, and do so at a
much higher level than neurons, although the H-chain-stained oligodendro-
cytes have a patchy distribution in white matter that parallels iron staining
[71, 72]. Astrocyt es are generally devoid of ferritin expression. From light
microscopy observations of nonheme iron in brain tissue [73], it has been
suggested that intracellular iron deposits are hemosiderin contained in
siderosomes [10], as ferritin in the cytosol only produces a pale blue
background. The reported nonuniformity of iron deposition in brain tissue
[73] is significant for magnetic resonance imaging (MRI) iron concentration
and T2 relaxation rate models, as it will lead to substantial variations in local
iron concentration at the cellular level. Detailed ultrastructural (electron
microscopy) studies have been performed of the nonuniform distribution of
ferritin and hemosiderin in iron-overloaded liver, but similar studies of brain
tissue are comparatively recent [55].
18.2.4 Iron Transport
Transferrin (Tf) is generally acknowledged as the primary protein responsible
for transporting iron from the blood into brain tissue, via transferrin receptors
NANOSCALE IRON COMPOUNDS RELATED TO NEURODEGENERATIVE DISORDERS 467