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Iron influx increases the translation of the Alzheimer amyloid precursor protein (APP) via an iron-responsive element (IRE)RNA Alzheimer disease (AD)3 is a neurodegenerative process that is the leading cause of death worldwide for people over the age of 65 (1, 2). The pathological hallmarks of AD in the brain cortex are not only abundant extracellular amyloid plaques (3) and intracellular tangles of the neurofibrillary protein tau but also increased brain iron (in ferritin-associated plaques) (4).The major component of these plaques is the 40 -42-amino acid ␤-amyloid (A␤) peptide cleaved from the amyloid precursor protein (APP) (5), which is the ubiquitously expressed trans-membrane metalloprotein (6). ␤-Secretase and ␥-secretases generate the 40 -42-amino acid A␤ peptide that is toxic to brain neurons, an event that is accelerated in the presence of iron (7-11). Intracellular iron levels control APP translation via iron-responsive 5Ј-untranslated region (APP 5Ј-UTR) sequences in the APP transcript (1, 12), likely mediated via internal ribosome entry mechanisms (13).In mammalian cells, iron homeostasis is regulated by posttranscriptional events by iron regulatory proteins (IRP1 and IRP2) that bind at high affinity to iron-responsive element (IRE) RNA hairpins and repress the translation of the iron storage protein ferritin as well as transcripts of other iron-associated proteins (14 -16). During conditions of iron influx, both IRP1 and IRP2 are released from the light (L) and heavy (H) ferritin IREs to increase the translational efficiency of the L-and H-chains of this intracellular iron storage multimer (17,18). Transferrin receptor (TfR) mRNA stability is controlled by five IREs (19,20) in its 3Ј-UTR, which binds IRP2 more avidly than IRP1 and thereby stabilizes TfR mRNA in a low intracellular iron milieu. Emerging evidence clearly supports iron directly interacting with the L-and H-ferritin IREs to weaken equal binding of IRP1-IRP2 (21).The canonical IRE stem loops encoded by L-and H-ferritin and TfR mRNAs are highly conserved throughout evolution. Similar 5Ј-UTR-specific IREs control the translation of Hif-2␣ (22), ferroportin (IREG-1) (23), the erythroid heme biosynthetic aminolevulinate synthase (eALAS) (24), and mitochondrial aconitase (25), each of which bind avidly to IRP1 to a greater degree than IRP2. In contrast to TfR mRNA, which binds at high affinity to IRP2, the duodenal divalent metal ion transporter (DMT1) (26) encodes an IRE stem loop immediately downstream from its stop codon and preferentially binds * This work was supported, in whole or in part, by National Institutes of Health Grant AG20181 (to J. T. R.). This work was also supported by a Zenith award from the Alzheimer's Association (to J. T. R.

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“…Perhaps this reflected disease-specific iron mobilization out of the brain via the blood-brain barrier (75). In the experiment shown in Fig.…”

Section: Discussionmentioning

confidence: 94%

Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1

Cho

Cahill

Vanderburg

et al. 2010

Journal of Biological Chemistry

154

190

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“…DISCUSSION Although there has been an increase in our understanding of iron transport and regulation of iron levels in hematopoietic tissue, macrophages, and enterocytes in the gut, there is little direct evidence for the molecular mechanisms underlying iron transport across neural cell membranes in the CNS (reviewed in Ref. 22). Once iron gets past the endothelial cells in the CNS, its uptake into neural cells could occur via transferrin and/or non-transferrin-mediated mechanisms.…”

Section: Resultsmentioning

confidence: 99%

Glycosylphosphatidylinositol-anchored Ceruloplasmin Is Required for Iron Efflux from Cells in the Central Nervous System

Jeong

David

2003

Journal of Biological Chemistry

331

289

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Ceruloplasmin (Cp) is a ferroxidase that converts highly toxic ferrous iron to its non-toxic ferric form. A glycosylphosphatidylinositol (GPI)-anchored form of this enzyme is expressed by astrocytes in the mammalian central nervous system, whereas the secreted form is expressed by the liver and found in serum. Lack of this enzyme results in iron accumulation in the brain and neurodegeneration. Herein, we show using astrocytes purified from the central nervous system of Cpnull mice that GPI-Cp is essential for iron efflux and not involved in regulating iron influx. We also show that GPI-Cp colocalizes on the astrocyte cell surface with the divalent metal transporter IREG1 and is physically associated with IREG1. In addition, IREG1 alone is unable to efflux iron from astrocytes in the absence of GPI-Cp or secreted Cp. We also provide evidence that the divalent metal influx transporter DMT1 is expressed by astrocytes and is likely to mediate iron influx into these glial cells. The coordinated actions of GPI-Cp and IREG1 may be required for iron efflux from neural cells, and disruption of this balance could lead to iron accumulation in the central nervous system and neurodegeneration.

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“…Intra-ischemic glutamate release in the penumbra zone correlates positively with increased free radical activity during reperfusion after transient middle cerebral artery occlusion [95]. These data indicate that high serum ferritin concentration may be a predictive factor of poor outcome following cerebral stroke [17,18,215,216]. In these studies, serum ferritin was measured within 24 hours of the event.…”

Section: Iron and Ischemic Strokementioning

confidence: 88%

“…Magnetic resonance imaging shows areas of increased iron deposition, suggesting that brain iron is disrupted after hypoxic-ischemic insult, leading to the increased accumulation of iron at its uptake sites [208]. In addition to the general participation of iron in ROS generation [122][123][124][125][126], recent data have revealed a link between the development of brain injury after ischemia and higher body iron stores [17,18,215,216]. High plasma ferritin, a reliable indicator of tissue iron [217,218], and high cerebrospinal fluid (CSF) ferritin have been related to poor outcomes in stroke patients [17-18, 215, 216].…”

Section: Iron and Ischemic Strokementioning

confidence: 99%

Iron, Oxidative Stress and Early Neurological Deterioration in Ischemic Stroke

Carbonell¹,

Rama

2007

CMC

135

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Ischemic stroke is characterized by the disruption of cerebral blood flow, which produces a central core of dead neurons surrounded by a penumbra of damaged but partially functional neurons. Many factors are associated with such brain injury, including excitotoxicity and free radicals. Recent clinical studies have shown that high plasma ferritin levels are detrimental in acute ischemic stroke. As an iron-storage protein, ferritin can act both as a scavenger and as a donor of free iron, which is a source of hydroxyl radicals. Following disruption of the blood-brain barrier, the ferritin and the free iron that have accumulated in endothelial cells in brain capillaries, together with plasma ferritin, can enter the penumbra. Iron-dependent oxidative stress in the penumbra can lead to necrosis and further neurological deterioration following ischemic stroke. An excess of iron should be considered pathological in the ischemic brain. Therapeutic strategies for ischemic stroke should attempt to restore brain function within the penumbra. Consequently, the iron content of systemic stores should be measured, and anti-oxidant treatment should be considered when it is excessive.

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Cited by 266 publications

References 114 publications

Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1

Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1

Glycosylphosphatidylinositol-anchored Ceruloplasmin Is Required for Iron Efflux from Cells in the Central Nervous System

Iron, Oxidative Stress and Early Neurological Deterioration in Ischemic Stroke

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