Myelin basic protein and transferrin characterize different subpopulations of oligodendrocytes in rat primary glial cultures

The iron transport glycoprotein, transferrin (Tf), localizes exclusively in oligodendrocytes in brain tissue sections. Previously, we showed that Tf is also expressed in oligodendrocytes in primary cultures established from newborn rat brains. Its developmental appearance precedes that of galactocerebroside (GC). In this study, Tf expression in primary brain cell cultures was investigated over a 4-week period in relation to GC and myelin basic protein (MBP), respectively, early and late markers of oligodendrocyte development. From 9 days in vitro and thereafter, all Tf+ cells were also found to be GC+. With increasing age the number of Tf+ cells decreased while the number of MBP+ cells increased. However, less than 10% of oligodendrocytes co-expressed Tf and MBP at any age. MBP+ cells were largely found in cell clusters which increased in size and number with age in culture. Interestingly, Tf+ cells were located around the clusters of MBP+ cells which displayed elaborate branched processes. The transient expression of Tf in oligodendrocytes which become MBP+, suggests a role for Tf in the early stages of myelinogenesis. The results also demonstrate the existence of three phenotypically distinct populations of oligodendrocytes. A new model of developmental and functional subpopulations of oligodendrocytes is proposed.     

The development of the transferrin-transferrin receptor system in relation to astrocytes, MBP and galactocerebroside in normal and myelin-deficient rat optic nerves

The factor(s) which control the onset of myelination are unknown. It is now accepted that transferrin (Tf), the major iron transport protein in vertebrates, is found in oligodendrocytes in the adult brain. Because of the importance of iron in basic cell metabolism we have hypothesized that iron (mobilized by Tf) may be a permissive agent in the process of myelination. The present study was designed to determine with immunohistochemistry the relationship of Tf receptor expression, Tf accumulation, and the expression of myelin components myelin basic protein (MBP) and galactocerebroside (GAlC)) in the developing rat optic nerve. In addition to Tf and its receptor, the developmental pattern for GalC reported in this study has not been examined in the rat optic nerve. Furthermore, a myelin mutant strain of rats was used to determine if a lack of myelin production affects the Tf-Tf receptor system. Our study found that Tf receptor was expressed from birth on blood vessels and was first seen in the parenchyma of the nerve at 8 days of age. The expression of the Tf receptor preceded that of Tf, MBP or GalC. The accumulation of Tf by oligodendrocytes occurred about the same time as the intracellular appearance of MBP and GalC which was shortly after the onset of myelination. Tf-positive cells as well as MBP- and GalC-positive cells increased in number and staining intensity with age whereas the expression of the Tf receptor declined after reaching a peak at 15 days of age. In the optic nerves of myelin-deficient rats, the Tf receptor expression and Tf accumulation was confined to the vasculature. The results of this study suggest that the expression of the Tf receptor is an early event in oligodendrocytic maturation and is followed by the intracellular accumulation of myelin components and Tf. The temporal association of Tf and myelin production suggests that further study is warranted regarding the possibility that the Tf-iron system supports or perhaps even permits the initiation of the process of myelination.     

The distribution of transferrin immunoreactivity in the rat central nervous system

Recent studies have demonstrated receptors in the nervous system for transferrin, the iron binding and transport protein in the blood. This study using immunohistochemistry at the light and electron microscopic levels demonstrates that transferrin (Tf) is found predominantly in oligodendrocytes in both the gray and white matter of the cerebral cortex, cerebellum and spinal cord. Within the cerebral cortex, layer V has more Tf-labeled cells than the other cortical layers. In the spinal cord, lamina VII has the highest density of Tf-positive cells. Based on location, 3 types of oligodendrocytes can be described: perineuronal, interfascicular and perivascular. In addition to oligodendrocytes, endothelial cells and possibly some neuronal membranes of layer V pyramidal and anterior horn cells label with Tf antiserum. Ultrastructurally, Tf reaction product is homogeneously distributed throughout the perinuclear cytoplasm of both oligodendrocytes and endothelial cells. The importance of iron in motor and behavior function is well established although the mechanism of action of iron in the CNS is not well understood. The presence of Tf in oligodendrocytes implies that these neuroglia are involved in iron mobilization and storage in the CNS. Stored quantities of iron and the ability to mobilize the iron through stored transferrin may be the reason for the extreme dietary restrictions necessary to induce iron-deficient CNS disorders.     

Embryonic divergence of oligodendrocyte and astrocyte lineages in developing rat cerebrum

Oligodendrocyte and astrocyte lineages were traced in rat forebrain sections using single- and double-label immunoperoxidase and indirect immunofluorescent techniques. Antibodies were directed against antigenic markers, the expressions of which overlapped in time: GD3 ganglioside in immature neuroectodermal cells; vimentin in radial glia; glial fibrillary acidic protein (GFAP) in astrocytes; and carbonic anhydrase (CA) and galactocerebroside (GC) in oligodendrocytes. A histochemical stain for iron was also used as a marker of oligodendrocytes. Small cells of the subventricular zone (SVZ) were stained with anti-GD3 but not with the other antibodies. By 16 d of gestation (E16), the SVZ generated large, round cells and thick, process-bearing cells that were GD3+/CA+/iron+. These cells then appeared in the cingulum and, with time, increased in numbers and extended thick processes as they filled the subcortical white matter. These cells eventually lost their reactivity to anti-GD3 but became GC+/CA+ with processes extending to myelin sheaths. At E15 radial glia were stained with the anti-vimentin antibody but were negative for GFAP. At birth, only the vimentin+ radial glia midline between the 2 ventricles were GFAP+, but with time more vimentin+ cells became GFAP+. By 7 d of postnatal age all the vimentin+ cells were GFAP+ and had converged predominately on the cingulum. With time these cells condensed and took on characteristic shapes of astrocytes. The embryonic separation of the oligodendrocyte and the astrocyte lineage is supported by four pieces of evidence: (1) GD3+ cells were double labeled with anti-CA, and then went on to become GC+; (2) vimentin+ and GFAP+ cells were not also GD3+; (3) ultrastructural localization of anti-GD3 was confined to cells with characteristics consistent with developing oligodendrocytes; and (4) the shapes of GD3+, CA+, GC+, or iron+ cells did not resemble those of the vimentin+ or GFAP+ cells.     

Development of transferrin-positive oligodendrocytes in the rat central nervous system

Transferrin is the second most abundant plasma protein and functions to transport iron. It is an essential constituent in culture media for virtually all cells. In a recent study, we reported that transferrin (Tf) is specifically located in oligodendrocytes in the rat nervous system. This investigation examines immunohistochemically the development of Tf in the cerebral cortex, corpus striatum, and spinal cord. Tf is first seen in oligodendrocytes in the spinal cord white matter at 5 days of age. The immunoreactivity is confined to the white matter in the periphery of the spinal cord between 5 and 8 days of age. By 10-12 days of age, the number of immunoreactive oligodendrocytes in the spinal cord white matter increases considerably, corresponding to the onset of myelination. Tf-positive oligodendrocytes are first found in the gray matter at 15 days of age. By 30 days of age, the number and distribution of Tf-positive oligodendrocytes in both the brain and spinal cord have reached the adult pattern. The results of this study demonstrate a spatial and temporal association between Tf development and myelinogenesis. This suggests that part of the process of differentiation of oligodendrocytes includes the accumulation of Tf, perhaps in order to support the metabolic demands associated with the production and maintenance of myelin.     

Oligodendrocyte differentiation is increased in transferrin transgenic mice

Transferrin (Tf), the iron transport glycoprotein found in biological fluids of vertebrates, is synthesized mainly by hepatocytes. Tf is also synthesized by oligodendrocytes (Ol), and several lines of evidence indicate that brain Tf could be involved in myelinogenesis. Because Tf is postnatally expressed in the brain, we sought to investigate whether Tf could intervene in Ol differentiation. For this purpose, we analyzed transgenic mice overexpressing the complete human Tf gene in Ol. We show that the hTf transgene was expressed only from 5 days postpartum onward. In the brain of 14-day-old transgenic mice, the DM-20 mRNA level was decreased, whereas the PLP, MBP, CNP, and MAG mRNA levels were increased. We counted a higher proportion of Ol expressing the O4 (Ol-specific antigens) and PLP in brain cells cultured from transgenic mice. These results support the idea that overexpressing Tf in the brain accelerates the oligodendrocyte lineage maturation. Accordingly, by NMR imaging acquisition of diffusion tensor in hTf transgenic mice, we observed early maturation of the cerebellum and spinal cord and more myelination in the corpus callosum. In addition, hTf overexpression led to an increase in Sox10 mRNA and protein. Increases in Sox10 and in Tf expression occur simultaneously during brain development. The Olig1 mRNA level also increased, but long after the rise of hTf and Sox10. The Olig2 mRNA level remained unchanged in the brain of transgenic mice. Our findings suggest that Tf could influence oligodendrocyte progenitor differentiation in the CNS.     

Transferrin gene expression and secretion by rat brain cells in vitro

We have previously shown by immunocytochemistry in rat primary glial cultures that transferrin (Tf) is an early developmental marker for oligodendrocytes. The present work addresses the issue of Tf gene expression and synthesis by neural cells in vitro. For this purpose, we used rat embryonic neuronal cultures and newborn glial cultures of astrocytes and oligodendrocytes. Cultured fibroblasts and C6 glioma cells were used as negative controls. We found that Tf mRNA is present in oligodendrocytes, astrocytes, and neurons. However, oligodendrocytes and astrocytes, but not neurons, were shown to synthesize and secrete Tf. Neither fibroblasts nor C6 glioma cells expressed detectable amounts of Tf mRNA. Tf mRNA levels in astrocyte cultures appeared to be under hormonal control since hydrocortisone markedly reduced message levels. These results show that both astrocytes and oligodendrocytes can synthesize and secrete Tf under cell culture conditions. However, epigenetic factors, such as hydrocortisone, may repress the expression of Tf in astrocytes in vivo.     

Immunocytochemical localization of transferrin and mitochondrial malate dehydrogenase in the developing nervous system of the rat

Transferrin accumulates within neurons of the developing nervous system of humans, sheep, pigs and chickens. To assess the relationship of this accumulation with the ontogeny of oxidative metabolism, we studied the immunocytochemical localization of transferrin (Tf) and the mitochondrial form of malate dehydrogenase (mMDH) in developing neural tissues by the peroxidase-antiperoxidase method. Rabbit anti-rat Tf was obtained commercially and gave a single band of reaction product (MW = 80 kd) on Western blots. Antibodies to porcine heart mMDH were elicited in a rabbit. Western blot analysis showed that this anti-porcine mMDH antibody reacted with the mMDH from porcine, rat or avian tissue but not with the cytosolic MDH from pigs. Tf was first detected in rat brain neurons at about the 18th embryonic day and reached a peak at about the 6th postnatal day. All neurons were immunoreactive with large neurons throughout the brain showing a strong reaction for Tf. From this time onward, the level in brain neurons gradually decreased until adulthood. However, Tf immunoreactivity still remained strongly evident in capillary endothelial cells. The localization of Tf within rat spinal cord neurons peaked as early as the 1st postnatal day and remained elevated to the 6th postnatal day. By contrast, reactivity for Tf within dorsal root ganglia neurons was intense as early as the 18th embryonic day and diminished only gradually. Mitochondrial MDH, a marker for oxidative metabolism, appeared to reach a peak after the crest of intraneuronal Tf had been observed. For example, brain and spinal cord MDH immunoreactivity increased with intense staining in the cell bodies and fibers of neurons from the 6th to the 13th postnatal day; immunoreactivity gradually diminished into adulthood. The gradient of reactivity was low in some areas of the brain but more intense in areas containing large neuronal cell bodies such as the red nucleus. This occurred after the peak of intraneuronal Tf at day 6 and suggested a precursor-product relationship. By contrast, immunoreactivity for neuron-specific enolase, a glycolytic enzyme, showed a developmental pattern that differed from either Tf or MDH in that reactivity appeared later in development and was less intense. These data suggest that as cerebral metabolic rates begin to increase as early as 5-6 days after birth in the rat, an increase in mMDH occurs coincident with the onset of oxidative metabolism. Furthermore, this rise in intraneuronal mMDH follows the peak of intraneuronal Tf and suggests that Tf supplies the iron required for the synthesis of other mitochondrial ferroproteins.     

Activation, proliferation and commitment of endogenous stem/progenitor cells to the oligodendrocyte lineage by TS1 in a rat model of dysmyelination

Wild-type and myelin-deficient rats received a single intraparenchymal injection of TS1, a specific combination of IGF-1 and transferrin (Tf), into their corpus callosum at postnatal day 4. The fate of endogenous stem cells in the brain was examined by the expression of the stem cell marker nestin, together with Tf, neurofilaments and glial fibrillary acidic protein from 2 to 14 days after injection. Treated mutants lacked nestin expression in the ventricular wall and had an increase in nestin-labeled radial cell processes in the subventricular regions, and extended into the parenchyma. The subventricular zone was populated by healthy new oligodendrocytes (OLs). BrdU incorporation showed that these cells originated by proliferation and were identified as OLs based upon Tf expression. Thus, TS1 is an effective treatment to promote endogenous subventricular zone progenitor proliferation, migration and OL lineage specification. This strategy offers for the first time the possibility of myelin restoration to treat myelin disorders.     

A new oligodendrocyte specific plasma membrane surface protein identified by a monoclonal antibody produced in vitro

This paper describes a novel monoclonal antibody (C1G5F2) derived from mice splenocytes immunized in vitro with a wheat germ agglutinin glycoprotein fraction isolated from bovine central nervous system (CNS) myelin. Immunohistochemical reactions with C1G5F2 were investigated on rat brain sections during the active period of myelination. From day 10 to 13 postnatally, no stained structures were observed throughout the whole brain. The first immunolabeled myelin fibers were detected within the pons at day 14, and the white matter areas in the cerebrum started to be stained some days later. White matter areas of the cerebellum were clearly immunopositive after the third week. There was a strong positive signal on myelin fibers in the cerebrum at day 30. By contrast, no immunolabeled cell bodies of oligodendrocytes were observed throughout the brain. The other neural cell types were also not labeled. This C1G5F2 monoclonal antibody bound mainly to the extracytosolic membrane surface of the processes of live cultured oligodendrocytes derived from newborn rat brain but was unreactive with live or fixed astrocytes and neurons maintained in culture. No immunostaining was detected in the peripheral nervous system or in the spleen, liver, or pancreas. The C1G5F2 epitope containing antigen may therefore be considered as a CNS myelin/oligodendrocyte specific molecule. Sodium deoxycholate-Tween 20 extracts of secondary oligodendrocyte cultures, biotinylated with biotin hydrazide, were used to attempt the purification of the antigen with C1G5F2 IgMs linked to antimouse IgM agarose. A main broad biotinylated protein band of 54–58 kDa molecular mass was noted. In a second approach, the antigen was immunopurified from cultured oligodendrocytes as an immune complex using biotinylated C1G5F2 IgMs. A distinct protein doublet of 53–56 kDa was also observed. It is postulated that this antigen may play an essential role in myelin formation and could be a possible target in diseases restricted to CNS myelin. © 1994 Wiley-Liss, Inc.     

Aluminum uptake and effects on transferrin mediated iron uptake in primary cultures of rat neurons, astrocytes and oligodendrocytes

Transferrin (Tf) is known primarily for its role in the transport and cellular uptake of iron (Fe). Tf is also the major serum binding protein for Al. In this study, primary rat oligodendrocyte, neuron and astrocyte cultures were found to differ in Tf mediated Fe and Al uptake and in the effect of Al-Tf on Fe-Tf uptake during 4 h incubation periods. When incubated with Al-Tf (1.25 microM), oligodendrocytes displayed a 3- to 4-fold increase (p=.0002) in Al, neurons demonstrated a much smaller (p=.06) increase, and no increase was seen for astrocytes. When incubated with equimolar Al citrate or Al chloride, no increase in cellular Al was seen in any of the three cell types. Oligodendrocytes, astrocytes and neurons all demonstrated greater 59Fe uptake from Fe-Tf than Fe chloride. This uptake could be inhibited by excess Fe-Tf in oligodendrocytes and neurons, but not astrocytes. A small but significant inhibition of 59Fe uptake from Fe-Tf was seen after addition of Al-Tf to the incubation medium of oligodendrocytes, but not neurons or astrocytes. Oligodendrocytes may be particularly vulnerable to the accumulation of excess intracellular Al, and to interference of Al with Fe uptake. Such effects could contribute to Al-induced neurotoxicity if they result in altered myelin formation or maintenance.     

Udpgalactose:Ceramide galactosyltransferase in cultured oligodendrocytes: An enzymological and immunological study

The developmental expression of UDPgalactosexeramide galactosyltransferase (CGalT), an enyme marker of one myelinogenic activity in nervous tissue, was studied in cultured oligodendrocytes. The activity of CGalT in cultures followed a characteristic pattern of developmental changes. In the primary cultures these changes could be represented by a biphasic curve with a maximum of enzymatic activity at about the 25th day in culture. After purifying the oligodendrocytes from the primary cultures and replating them in culture dishes, similar developmental changes of CGalT were observed. In the subultures prepared from 20-day-old primary cultures the activity of CGalT per oligodendrocyte increased from 1.3 × 10⁻⁶ nmol/hr on day 4 to 3.7 × ⁻⁶ nmol/hr on day 21. Immunocytochemical studies with the antiserum against rat brain CGalT showed the presence of CGalT⁺ oligodendrocytes after 7 days in the primary culture (earliest time studied), later on the number of CGalT⁺ oligodendrocytes increased until 28 days (latest time examined). In the subcultures of purified oligodendrocytes the bulk of oligodendrocytes was stained by the anti-CGalT antibodies after 15 days. These results suggest that the initial expression of CGalT in oligodendroglial cultures involves an increase of the number of CGalT⁺ oligodendrocytes and of the amount of enzyme protein per cell.     

Transferrin is an early marker of hepatic differentiation,and its expression correlates with the postnatal development of oligodendrocytes in mice

Transferrin (Tf), the iron transport protein, is essential for the growth and differentiation of cells. Therefore, it provides an excellent model to analyze the regulatory mechanisms controlling the expression of a eukaryotic gene in different cell types and during fetal and adult life. In this study, the tissue-specific and developmental regulation of the Tf gene in vivo were analyzed. Human Tf mRNA was detected mainly in fetal and adult liver. A weaker expression was observed in adult and fetal brain and in fetal spleen. By in situ hybridization the presence of mouse Tf mRNA was detected in the hepatic primordia. This is the first observation pointing out Tf as an early marker of hepatic differentiation, prior to the formation of the liver. Thus, TF may be an important tool to follow the hepatic specification of the gut endoderm. Mouse Tf mRNA was also detected in the liver bud and subsequently in the liver throughout fetal life, and in newborn and adult animals. No expression of the Tf gene was observed in the mouse fetal central nervous system (CNS). In contrast, Tf mRNA was detected from the 5th day after birth in the derivatives of the caudal part of the neural tube and subsequently in the derivatives of the rhomboencephalon and that of the prosencephalon. These results indicate that Tf gene expression correlates with the postnatal development of oligodendrocytes in the mouse CNS. To test whether the control elements of the human gene previously found in ex vivo experiments were also active in vivo during fetal and adult life, we fused the −4000/+39 5′ flanking region of the human gene to the coding region of the lacZ gene and generated transgenic mice. The expression of the reporter gene during development was analyzed. J. Neurosci. Res. 50:421–432, 1997. © 1997 Wiley-Liss, Inc.     

Iron is essential for oligodendrocyte genesis following intraspinal macrophage activation

Progenitor proliferation and differentiation are necessary for oligodendrocyte replacement. Previously, we showed that intraspinal activation of microglia and macrophages with the TLR4 agonist lipopolysaccharide (LPS) induced robust oligodendrocyte genesis. In this study we investigated whether this process involves iron since LPS can alter macrophage regulation of iron and its storage protein ferritin, and oligodendrocytes require iron for proper development and myelination. Further, activated macrophages can sequester and release iron and ferritin. We first examined whether iron or ferritin was present following LPS microinjection. Using Perl's stain, we noted a slight increase in iron at 1d, and peak iron levels 3d post-injection coincident with maximal macrophage activation. Ferritin+ cells were prevalent by 3d and included macrophages and NG2 cells (putative oligodendrocyte progenitors). At 7d, ferritin was mainly expressed by new oligodendrocytes prevalent throughout the lesions. Because of the timing and distribution of iron and ferritin after LPS, we next used an iron chelator to test whether free iron was necessary for maximal LPS-induced oligodendrocyte genesis. Chelating iron by Deferasirox (Exjade®) after LPS microinjection significantly reduced the number of proliferating NG2 cells and new oligodendrocytes. Of the remaining oligodendrocytes, there was a 2-fold decrease in those expressing ferritin, revealing that the number of oligodendrocytes with high iron stores was reduced. Collectively, these results establish that iron accumulates after intraspinal TLR4 activation and is required for maximal TLR4-induced oligodendrogenesis. Since TLR4 agonists are abundant in CNS injury/disease sites, these results suggest that iron may be essential for macrophage/oligodendrocyte communication and adult glial replacement.     

Time- and cell-type speciifc changes in iron,ferritin, and transferrin in the gerbil hippocampal CA1 region after transient forebrain ischemia

In the present study, we used immunohistochemistry and western blot analysis to examine changes in the levels and cellular localization of iron, heavy chain ferritin (ferritin-H), and transferrin in the gerbil hippocampal CA1 region from 30 minutes to 7 days following transient forebrain ischemia. Relative to sham controls, iron reactivity increased signiifcantly in the stratum pyramidale and stratum oriens at 12 hours following ischemic insult, transiently decreased at 1–2 days and then increased once again within the CA1 region at 4–7 days after ischemia. One day after ischemia, ferritin-H immunoreactivity increased significantly in the stratum pyramidale and decreased at 2 days. At 4–7 days after ischemia, ferritin-H immunoreactivity in the glial components in the CA1 region was signiifcantly increased. Transferrin im-munoreactivity was increased signiifcantly in the stratum pyramidale at 12 hours, peaked at 1 day, and then decreased signiifcantly at 2 days after ischemia. Seven days after ischemia, Transferrin immunoreactivity in the glial cells of the stratum oriens and radiatum was signiifcantly increased. Western blot analyses support-ed these results, demonstrating that compared to sham controls, ferritin H and transferrin protein levels in hippocampal homogenates significantly increased at 1 day after ischemia, peaked at 4 days and then decreased. These results suggest that iron overload-induced oxidative stress is most prominent at 12 hours after ischemia in the stratum pyramidale, suggesting that this time window may be the optimal period for therapeutic intervention to protect neurons from ischemia-induced death.     

Thrombin preconditioning attenuates brain edema induced by erythrocytes and iron.

Pretreatment with a low intracerebral dose of thrombin reduces brain edema after hemorrhagic and thrombo-embolic stroke. We have termed this phenomena thrombin preconditioning (TPC) or thrombin-induced brain tolerance. Red blood cell lysis and iron overload contribute to delayed edema formation after intracerebral hemorrhage. The present study examined whether TPC can attenuate the brain edema induced by lysed red blood cells or iron. It also examined whether TPC is associated with increasing hypoxia inducible factor-1alpha (HIF-1alpha) levels and alterations in two HIF-1alpha target genes, transferrin (Tf) and transferrin receptor (TfR), within the brain. Brain edema was measured by wet/dry weight method. HIF-1alpha, Tf, and TfR were measured by Western blot analysis and immunohistochemistry. We found that TPC reduces the edema induced by infusion of lysed red blood cells and iron. Thrombin increases HIF-1alpha levels through p44/42 mitogen activated protein kinases pathway. Thrombin also increases Tf and TfR levels in the brain. These results indicate that HIF-1alpha and its target genes may be involved in thrombin-induced brain tolerance.     

Transferrin receptors in the normal human hippocampus and in Alzheimer's disease

Several lines of evidence suggest that aluminium may play a role in the pathogenesis of Alzheimer's disease (AD). The iron transport protein transferrin is the major transport protein for aluminium, and aluminium gains access to cells by means of a specific cell surface transferrin receptor. We have assessed the distribution of transferrin receptors in the normal and AD hippocampal formation using [³H]–transferrin ([³H]–Tf) binding and tritium film autoradiography, in order to assess the role of the transferrin receptor in AD. In normal brain, ³H]–Tf binding was highest in the pyramidal cell layers with CA2> dentate gyrus granule cell layer ≥Cal >CA3 ≥ CA4>subiculum>parahippocampal gyrus. In AD, significant reductions in [³H]–Tf binding were found in CA1, CA2 and CA4 pyramidal cell layers. The reduced [³H]–Tf binding in AD may, however, be due to poor pre–mortem agonal states which correlated with reduced [³H]–Tf binding. The discrepancy between the distribution of transferrin receptors in the hippocampus and those areas which are prone to the formation of senile plaques and neurofibrillary tangles suggests that if transferrin–mediated uptake of aluminium in AD/SDAT is significant in the pathogenesis of this disorder, it is not the only determinant of Alzheimer–type neuropathology.     

Patterns of immunocytochemical staining for ferritin and transferrin in the human spinal cord following traumatic injury.

Normally Fe(2+) is strictly controlled within the central nervous system (CNS) because of its potential to react with oxygen and form free radicals.(1,2) Traumatic spinal cord injury (TSCI) leads to cell damage and haemorrhage, both of which may increase the pool of free iron.(3) The aim of this study was to examine the response to TSCI of the iron storage protein ferritin (Ft) and the iron transport protein transferrin (Tf). The study found a significant increase in Ft positive cells compared to controls and a significant correlation between the number of Ft positive cells and the severity of injury. Significantly fewer Tf positive cells were seen in the trauma cases compared to the control and there was no relation with the severity of injury. These observations suggest a disturbance in normal iron metabolism within the spinal cord following injury, with possible implications for free radical mediated secondary damage.