Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system

Moos, Torben

doi:10.1002/(sici)1096-9861(19961125)375:4<675::aid-cne8>3.0.co;2-z

Cited by 152 publications

(112 citation statements)

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“…Astrocytes occupy discrete nonoverlapping domains, with blood vessels lying along the boundaries of these domains (Nedergaard et al, 2003) whereas neurons lie within and between these domains. We have shown previously that astrocytes are capable of nontransferrin-bound iron uptake in vitro (Jeong and David, 2003), which may be mediated via the influx transporter DMT1 (Burdo et al, 1999;Williams et al, 2000;Jeong and David, 2003) or also possibly TfR1, although there is conflicting evidence for the latter (Roskams and Connor, 1992;Moos, 1996;Qian et al, 1999), and our own immunostaining does not show expression of TfR1 in these glia. In addition, astrocytes also express FPN1 (Burdo et al, 2001) and GPI-Cp (Patel et al, Jeong and David, 2003), which are required for iron efflux.…”

Section: Role Of Astrocytes In Iron Trafficking In the Cnsmentioning

confidence: 43%

“…4A-C) and in the large neurons of the deep nuclei (Fig. 5A-C (Moos, 1996), we were unable to detect expression of TfR1, the other iron uptake mechanism, in Purkinje neurons in our mice. Interestingly, although expression of TfR1 is not increased in Purkinje cells in 24-month-old Cp Ϫ/Ϫ mice, it appears to be elevated in endothelial cells compared with age-matched controls (Fig.…”

Section: Changes In Expression Of Iron Homeostasis Proteinsmentioning

confidence: 59%

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Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Jeong¹,

David²

2006

J. Neurosci.

130

145

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Iron is essential for a variety of cellular functions, but its levels and bioavailability must be tightly regulated because of its toxic redox activity. A number of transporters, binding proteins, reductases, and ferroxidases help maintain iron homeostasis to prevent cell damage. The multi-copper ferroxidase ceruloplasmin (Cp) converts toxic ferrous iron to its nontoxic ferric form and is required for iron efflux from cells. Absence of this enzyme in humans leads to iron accumulation and neurodegeneration in the CNS. Here we report on the changes that occur in the cerebellum of Cp null (Cp Ϫ/Ϫ ) mice with aging. We show that iron accumulation, which is reflected in increased ferritin expression, occurs mainly in astrocytes by 24 months in Cp Ϫ/Ϫ mice and is accompanied by a significant loss of these cells. In contrast, Purkinje neurons and the large neurons in the deep nuclei of Cp Ϫ/Ϫ mice do not accumulate iron but express high levels of the iron importer divalent metal transporter 1, suggesting that these cells may be iron deprived. This is also accompanied by a significant reduction in the number of Purkinje neurons. These data suggest that astrocytes play a central role in the acquisition of iron from the circulation and that two different mechanisms underlie the loss of astrocytes and neurons in Cp Ϫ/Ϫ mice. These findings provide a better understanding of the degenerative changes seen in humans with aceruloplasminemia and have implications for normal aging and neurodegenerative diseases in which iron accumulation occurs.

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Section: Role Of Astrocytes In Iron Trafficking In the Cnsmentioning

confidence: 43%

Section: Changes In Expression Of Iron Homeostasis Proteinsmentioning

confidence: 59%

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Jeong¹,

David²

2006

J. Neurosci.

130

145

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“…Indeed, excessive iron deposition is observed in the central nervous system (CNS) in a number of neurodegenerative diseases [4][5][6]. Iron uptake in the brain is tightly controlled by transferrin receptor in the endothelial cells and choroid plexus cells [7], or lactoferrin receptor on neurons [8,9]. For the export of iron from neurons or non-neuronal cells, a brain-specific ceruloplasmin is suggested to play a role [10,11].…”

Section: Introductionmentioning

confidence: 99%

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

et al. 2007

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Although iron is essential in maintaining the function of the central nervous system, it is a potent source of reactive oxygen species. Excessive iron accumulation occurs in many neurodegenerative diseases including Alzheimer disease (AD), Parkinson's disease, and Creutzfeldt-Jakob disease, raising the possibility that oxidative stress is intimately involved in the neurodegenerative process. AD in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.

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“…Connor and Menzies [6] have shown in their immuno-histochemistry studies that TfR is expressed in neurons and to a less extent in neuroglia. Moos [12], on the other hand, reported a negative immunoreactivity of TfR in astrocytes, oligodendrocytes, or microglial cells. Our studies by Northern blot of TfR mRNA show that astrocytes do express TfR mRNA; but in a capability much weaker than PC12 cells or choroidal epithelial cells.…”

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confidence: 99%

Iron overload following manganese exposure in cultured neuronal, but not neuroglial cells

Zheng

Zhao

2001

Brain Research

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Our previous studies show that manganese (Mn) exposure inhibits aconitase, an enzyme regulating the proteins responsible for cellular iron (Fe) equilibrium. This study was performed to investigate whether Mn intoxication leads to an altered cellular Fe homeostasis in cultured neuronal or neuroglial cells as a result of disrupted Fe regulation. Our results reveal a significant increase in the expression of transferrin receptor (TfR) mRNAs and a corresponding increase in cellular 59 Fe net uptake by PC12 cells, but not astrocytes, following Mn exposure. These findings suggest that alteration by Mn of cellular Fe homeostasis may contribute to Mn-induced neuronal cytotoxicity. KeywordsManganese; Iron; Transferrin receptor; Transferrin receptor mRNA; uptake; PC12 cell; Astrocyte Intracellular iron homeostasis is post-translationally regulated by one of the iron regulatory proteins (IRPs), namely cytoplasmic aconitase (ACO1) or IRP-I. This protein contains a unique [4Fe-4S] cubane cluster in its active catalytic site, with one particularly labile Fe atom. ACO1 can selectively bind to mRNAs containing a stem-loop structure, also referred to as iron responsive elements (IRE) [4,11]. In iron-replete cells, ACO1 secures iron as part of its structure in the form of a [4Fe-4S] cluster. While this form of ACO1 binds poorly to mRNA, it can enzymatically catalyze the conversion of bound citrate to isocitrate. When cellular iron levels are insufficient, ACO1 assumes a [3Fe-4S] configuration, loses its cluster and enzymatic activity, and is transformed into an mRNA-binding protein. In the latter state, the enzyme binds with high affinity to IRE-containing mRNAs, inhibits translation of those mRNAs whose IRE's are 5′ (e.g., ferritin, succinic dehydrogenase, mitochondrial aconitase), and stimulates the expression of those whose IRE's are 3′ (e.g., transferrin receptor). The net result of this RNA-protein interaction is an increase in cellular Fe uptake and a decrease in Fe storage [4,9,11].Our previous studies indicate that Mn exposure significantly alters cellular aconitase activity [19]. This may be primarily due to a close mimicry between Mn and Fe in their coordination chemistry, allowing Mn to compete with Fe and insert itself into the fourth, labile Fe binding site in the enzyme's active center. We postulate that such replacement, while suppressing ACO1's enzymatic catalytic function, would increase the protein's ability to bind to mRNAs encoding transferrin receptor (TfR), which in concert with a down-regulation of Fe storage . The cells were plated in 24-well (4 cm 2 /well) trays and incubated in RPMI 1640 medium (ATCC) with 2 mM L-glutamine, 1.5 g/l sodium bicarbonate, 4.5 g/l glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 10% heat-inactivated horse serum, and 5% FBS. The medium was changed every 2-3 days. A primary culture of astrocytes was established according to the procedure described by Goodman et al., [7]. The cerebral cortices of newborn SpragueDawley rats (Hilltop, Cottdale, PA) were removed and minced wi...

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Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system

Cited by 152 publications

References 45 publications

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

Iron overload following manganese exposure in cultured neuronal, but not neuroglial cells

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