The role of iron in brain ageing and neurodegenerative disorders

In the paper

“The inflammatory milieu associated with multiple sclerosis includes the activation of microglia and subsequent release of proinflammatory cytokines and ROS, inducing oxidative stress.40”

What the sources say

• Not checked yetcites [40] Williams, 2012, Pathogenic implications of iron accumulation in multiple sclerosis, J Neurochem source

In the paper

“In other rare genetic diseases of this group, such as pantothenate kinase-associated neurodegeneration, phospholipase A2G6-associated neurodegeneration, and Kufor-Rakeb disease, mutations disrupt proteins with cellular functions different from iron metabolism, and the mechanisms that result in brain iron overload are undefined.169–173”

What the sources say

• Not checked yetcites [169] Schipper, 2012, Neurodegeneration with brain iron accumulation–clinical syndromes and neuroimaging, Biochim Biophys Acta source
• Not checked yetcites [170] Rouault, 2013, Iron metabolism in the CNS: implications for neurodegenerative diseases, Nat Rev Neurosci source
• Not checked yetcites [171] Dusek, 2012, Neurodegeneration with brain iron accumulation, Curr Opin Neurol source
• Not checked yetcites [172] Gregory, 2011, Genetics of neurodegeneration with brain iron accumulation, Curr Neurol Neurosci Rep source
• Not checked yetcites [173] Schneider, 2013, Genetics and pathophysiology of neurodegeneration with brain iron accumulation (NBIA), Curr Neuropharmacol

In the paper

“In these iron overloaded areas of the brain, up to a ten-times increase was recorded in neurons and microglia, but widespread brain iron deposition can occur.170,175”

What the sources say

• Not checked yetcites [170] Rouault, 2013, Iron metabolism in the CNS: implications for neurodegenerative diseases, Nat Rev Neurosci source
• Not checked yetcites [175] Kruer, 2012, Neuroimaging features of neurodegeneration with brain iron accumulation, AJNR Am J Neuroradiol source

In the paper

“Pantothenate kinase-associated neurodegeneration is characterised by an excess of iron especially in the globus pallidus, leading to a typical MRI pattern called eye of the tiger, and to a lesser extent, and later in the disease, in the substantia nigra.174,175”

What the sources say

• Not checked yetcites [174] Kruer, 2011, Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration, Brain source
• Not checked yetcites [175] Kruer, 2012, Neuroimaging features of neurodegeneration with brain iron accumulation, AJNR Am J Neuroradiol source

In the paper

“The major consequences of frataxin deficiencies include the impairment of mitochondrial biosynthesis of proteins containing iron–sulphur clusters (eg, aconitase), deficiency of respiratory chain electron transporters on complexes I–III, iron overload in mitochondria, oxidative stress, and free radical accumulation leading to changes in cellular iron metabolism.164,165”

What the sources say

• Not checked yetcites [164] Pandolfo, 2012, Friedreich ataxia: new pathways, J Child Neurol source
• Not checked yetcites [165] Ye, 2010, Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease, Biochemistry source

In the paper

“Typical iron accumulation in phospholipase A2G6-associated neurodegeneration often occurs in the globus pallidus and might affect the substantia nigra.178”

What the sources say

• Not checked yetcites [178] Kurian, 2008, Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN), Neurology source

In the paper

“MRI iron patterns in Kufor-Rakeb disease are controversial, with iron deposition in the putamen and caudate nucleus in some cases,181 or without discernible iron deposition in other individuals.182”

What the sources say

• Not checked yetcites [181] Schneider, 2010, ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation, Mov Disord source
• Not checked yetcites [182] Chien, 2011, ATP13A2-related neurodegeneration (PARK9) without evidence of brain iron accumulation, Mov Disord source

In the paper

“Fatty acid hydroxylase-associated neurodegeneration leads to iron accumulation in the globus pallidus, with the substantia nigra possibly less affected.172”

What the sources say

• Not checked yetcites [172] Gregory, 2011, Genetics of neurodegeneration with brain iron accumulation, Curr Neurol Neurosci Rep source

In the paper

“Iron misregulation is implicated in the pathology of restless leg syndrome, so that concentrations of TFR, IRP1, DMT1, ferroportin, and heavy-chain ferritin are decreased in dopaminergic neurons of the substantia nigra.198–200”

What the sources say

• Not checked yetcites [198] Allen, 2007, The role of iron in restless legs syndrome, Mov Disord source
• Not checked yetcites [199] Connor, 2003, Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome, Neurology source
• Not checked yetcites [200] Connor, 2004, Decreased transferrin receptor expression by Neuromelanin cells in restless legs syndrome, Neurology source

In the paper

“Iron deficit conditions worsen symptomatology, whereas iron replacement therapy improves symptoms.198,201”

What the sources say

• Not checked yetcites [198] Allen, 2007, The role of iron in restless legs syndrome, Mov Disord source
• Not checked yetcites [201] Ondo, 2010, Intravenous iron dextran for severe refractory restless legs syndrome, Sleep Med source

In the paper

“In embryonic stem cells, huntingtin is iron-regulated and also involved in iron homoeostasis regulation.193”

What the sources say

• Not checked yetcites [193] Hilditch-Maguire, 2000, Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles, Hum Mol Genet source

In the paper

“By contrast, a more general involvement of deep grey matter nuclei (and grey matter in general) with respect to iron accumulation is seen in aceruloplasminaemia, but without evidence of cystic processes.191”

What the sources say

• Not checked yetcites [191] Fasano, 2008, Aceruloplasminemia: a novel mutation in a family with marked phenotypic variability, Mov Disord source

In the paper

“MRI studies of neuroferritinopathy have suggested that the greatest accumulation of iron is in the basal ganglia and dentate nuclei, but thalamus and red nuclei can also be affected.185,189,190”

What the sources say

• Not checked yetcites [185] Chinnery, 2007, Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation, Brain source
• Not checked yetcites [189] Ohta, 2012, MRI findings in neuroferritinopathy, Neurol Res Int source
• Not checked yetcites [190] McNeill, 2012, Progressive brain iron accumulation in neuroferritinopathy measured by the thalamic T2* relaxation rate, AJNR Am J Neuroradiol source

In the paper

“High-field MRI amplifies the paramagnetic effect of iron on T2* relaxation, leading to improved sensitivity, resolution,202 and a better resolution of confounding factors.”

What the sources say

• Not checked yetcites [202] Duyn, 2012, The future of ultra-high field MRI and fMRI for study of the human brain, Neuroimage source

In the paper

“Mouse models of neuroferritinopathy show iron overload, neurodegeneration, and DNA damage.187,188”

What the sources say

• Not checked yetcites [187] Vidal, 2008, Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice, J Neurosci source
• Not checked yetcites [188] Deng, 2010, Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy, Neurosci Lett source

In the paper

“Myelin and iron decrease T2*, but have an opposing effect on frequency owing to the diamagnetic properties of myelin (as opposed to iron’s paramagnetic properties).204”

What the sources say

• Not checked yetcites [204] Duyn, 2013, MR susceptibility imaging, J Magn Reson source

In the paper

“Patients receiving 250 mg/day showed a substantial reduction in CSF of Aβ concentration, and some cognitive improvement (executive function) was noted.219”

What the sources say

• Not checked yetcites [219] Lannfelt, 2008, Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial, Lancet Neurol source

In the paper

“After 6 months many of the symptoms had improved, and after 1 year an improvement was recorded in the Unified Parkinson’s Disease Rating Scale score. T2*-weighted MRI showed a rapid decrease in iron accumulation in the bilateral dentate nuclei, with a milder and later reduction in the substantia nigra, but no significant changes in the red nuclei.213”

What the sources say

• Not checked yetcites [213] Kwiatkowski, 2012, Long-term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation, Parkinsonism Relat Disord source

In the paper

“In-vivo and post-mortem investigations suggest focal iron accumulation in the white matter in multiple sclerosis160,161,206 and focal iron accumulation in the cortex in amyotrophic lateral sclerosis207 co-localise with microglia (appendix).160,207”

What the sources say

• Not checked yetcites [160] Bagnato, 2011, Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla, Brain source
• Not checked yetcites [161] Yao, 2012, Chronic multiple sclerosis lesions: characterization with high-field-strength MR imaging, Radiology source
• Not checked yetcites [206] Bian, 2013, A serial in vivo 7T magnetic resonance phase imaging study of white matter lesions in multiple sclerosis, Mult Scler source
• Not checked yetcites [207] Kwan, 2012, Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology, PLoS One source

In the paper

“In the second clinical trial of deferiprone, patients with Parkinson’s disease received 20 mg/kg per day or 30 mg/kg per day for 6 months; both doses were well tolerated, there were minimum toxic effects, and decreases in iron in specific brain regions were detected by T2*-weighted MRI.216”

What the sources say

• Not checked yetcites [216] Dexter, 2013, Altered brain iron homeostasis in Parkinson's disease and potential for iron chelation therapy, Am J Hematol

In the paper

“Chelation therapy has been reported to provide improvements, notably with deferiprone, and particularly for other neurodegeneration with brain iron accumulation diseases, but no improvement was seen in two patients with neuroferritinopathy.185”

What the sources say

• Not checked yetcites [185] Chinnery, 2007, Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation, Brain source

In the paper

“deferoxamine (20 mg/kg per day for 5 days a week for 8 months by subcutaneous bolus injection) evoked an increase in urinary iron excretion, a decrease in serum ferritin concentrations, and decreases in haemoglobin iron and serum iron.224 By contrast, deferiprone 75 mg/kg per day for 6 months had no effect; no MRI changes were seen in the brain regions after either chelation therapy.224”

What the sources say

• Not checked yetcites [224] Mariani, 2004, Iron chelation therapy in aceruloplasminaemia: study of a patient with a novel missense mutation, Gut source

In the paper

“Velasco-Sanchez and colleagues220 administered deferiprone (20 mg/kg per day) and the antioxidant idebenone for 11 months to 20 patients with Friedreich’s ataxia aged between 8 and 25 years. MRI values in the dentate nuclei of participants showed a significant reduction of iron that was associated with significant recovery of kinetic functions, although gait and posture scores worsened.”

What the sources say

• Not checked yetcites [220] Velasco-Sánchez, 2011, Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia, Cerebellum source

In the paper

“A reduction in iron content was seen after 2 months of treatment and the effect was proportional to the concentration of initial accumulated iron.”

What the sources say

• Not checked yetcites [210] Boddaert, 2007, Selective iron chelation in Friedreich ataxia: biologic and clinical implications, Blood source

In the paper

“Treatment with 20 mg/kg per day or 30 mg/kg per day deferiprone for 6 months in nine patients with Friedreich’s ataxia aged between 14 and 23 years reduced the iron content in the dentate nuclei. This reduction was associated with neurological improvements in manipulative dexterity, speech fluency, and a reduction in neuropathy and ataxia gait, particularly in the youngest patients.”

What the sources say

• Not checked yetcites [210] Boddaert, 2007, Selective iron chelation in Friedreich ataxia: biologic and clinical implications, Blood source

In the paper

“Three of the 40 patients in the first study developed neutropenia or agranulocytosis, which were resolved rapidly with cessation of deferiprone.214,215”

What the sources say

• Not checked yetcites [214] Devos, 2012, Disease modifying strategy based upon iron chelation in Parkinson's disease: a translational study, Neurology
• Not checked yetcites [215] Moreau, 2013, Targeting brain chelatable iron as a therapeutic strategy for Parkinson's disease. Translational and clinical studies, Am J Hematol

In the paper

“An absence of ceruloplasmin can result in iron accumulation in the brain and neurodegeneration.17”

What the sources say

• Not checked yetcites [17] Jeong, 2003, Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system, J Biol Chem source

In the paper

“Iron is involved in many fundamental biological processes in the brain including oxygen transportation, DNA synthesis, mitochondrial respiration, myelin synthesis, and neurotransmitter synthesis and metabolism.1”

What the sources say

• Not checked yetcites [1] Crichton, 2009

In the paper

“Two cytosolic iron sensors, the iron regulatory proteins (IRPs) IRP1 and IRP2 (panel; appendix), regulate iron metabolism post-transcriptionally.12”

What the sources say

• Not checked yetcites [12] Wallander, 2006, Molecular control of vertebrate iron homeostasis by iron regulatory proteins, Biochim Biophys Acta source

In the paper

“Neurons are thought to acquire most of their iron via the transferrin–TFR system, and it is likely that they can export iron via ferroportin because many neurons co-express TFR and ferroportin.22”

What the sources say

• Not checked yetcites [22] Boserup, 2011, Heterogenous distribution of ferroportin-containing neurons in mouse brain, Biometals source

In the paper

“Iron crosses the vascular endothelial cells of the blood–brain barrier, mainly bound to transferrin via the transferrin–TFR1 system; TFR1 is highly expressed on the luminal side of endothelial cells.20”

What the sources say

• Not checked yetcites [20] Jefferies, 1984, Transferrin receptor on endothelium of brain capillaries, Nature source

In the paper

“Iron released in the extracellular compartment could then be taken up by other cells, such as astrocytes and neurons, either as low molecular weight complexes (eg, citrate, ATP, ascorbate) or after binding to transferrin via the transferrin–TFR pathways in neurons.16”

What the sources say

• Not checked yetcites [16] Leitner, 2012, Functional roles of transferrin in the brain, Biochim Biophys Acta source

In the paper

“In healthy ageing, selective accumulation of iron occurs in several brain regions and cell types, with iron mainly bound within ferritin and neuromelanin (panel).5,6”

What the sources say

• Not checked yetcites [5] Zecca, 2001, Iron, Neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes, J Neurochem source
• Not checked yetcites [6] Zecca, 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging, Proc Natl Acad Sci USA source

In the paper

“Astrocytes do not express TFR, but might take up iron at the blood–brain barrier via DMT1, which is expressed at the end-foot processes associated with the blood–brain barrier.26”

What the sources say

• Not checked yetcites [26] Xu, 1994, Studies of the ultrastructure and permeability of the blood-brain barrier in the developing corpus callosum in postnatal rat brain using electron dense tracers, J Anat

In the paper

“Transferrin is synthesised in the brain by the choroid plexus and by oligodendrocytes, but is only secreted in the choroid plexus.16”

What the sources say

• Not checked yetcites [16] Leitner, 2012, Functional roles of transferrin in the brain, Biochim Biophys Acta source

In the paper

“Peripheral cellular iron uptake mainly involves endocytosis of the diferric transferrin–transferrin receptor 1 (TFR1; panel) complex; iron is then transported from the endosomes into the cell cytoplasm via the divalent metal ion transporter 1 (DMT1; panel).”

What the sources say

• Not checked yetcites [1] Crichton, 2009
• Not checked yetcites [2] Hentze, 2010, Two to tango: regulation of Mammalian iron metabolism, Cell source
• Not checked yetcites [8] Mills, 2010, Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders, Future Med Chem source

In the paper

“Iron continually moves between neurons, microglia, and astrocytes, but how these cells acquire and release iron is not fully understood.21”

What the sources say

• Not checked yetcites [21] Zucca, 2011, The role of iron in neurodegeneration

In the paper

“When iron concentrations exceed the cellular iron sequestration capacity of storage proteins or other molecules, the concentration of iron in the labile iron pool (panel) can increase, which could be harmful and lead to oxidative damage and cell death.4”

What the sources say

• Not checked yetcites [4] Kruszewski, 2003, Labile iron pool: the main determinant of cellular response to oxidative stress, Mutat Res source

In the paper

“In many mammalian tissues (eg, hepatocytes and macrophages), cellular iron homoeostasis is regulated at the level of the translation of the mRNAs of proteins involved in iron metabolism, such as TFR1, DMT1, ferritin, and ferroportin.11”

What the sources say

• Not checked yetcites [11] Muckenthaler, 2008, Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network, Annu Rev Nutr source

In the paper

“MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases.”

In the paper

“As circulating iron concentrations decrease, hepcidin synthesis decreases, and iron exportation by ferroportin resumes.1,9,10”

What the sources say

• Not checked yetcites [1] Crichton, 2009
• Not checked yetcites [9] Andrews, 2008, Forging a field: the golden age of iron biology, Blood source
• Not checked yetcites [10] Garrick, 2009, Cellular iron transport, Biochim Biophys Acta source

In the paper

“Moreover, hepcidin concentrations rapidly increased in astrocytes and microglia after activation with the inflammatory stimuli, although hepcidin was undetectable in neurons.”

What the sources say

• Not checked yetcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source

In the paper

“No change in iron content was detected in astrocytes, although DMT1 increased after stimulus, and only lipopolysaccharide induced a small decrease in ferroportin concentrations.36”

What the sources say

• Not checked yetcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source

In the paper

“Glial iron accumulation can also induce an inflammatory state through an increased release of pro-inflammatory cytokines40 and result in a self-propelling cycle of neuroinflammation and neurodegeneration.41”

What the sources say

• Not checked yetcites [40] Williams, 2012, Pathogenic implications of iron accumulation in multiple sclerosis, J Neurochem source
• Not checked yetcites [41] Xu, 2012, Impaired iron status in aging research, Int J Mol Sci source

In the paper

“In the substantia nigra, ferritin heavy chain and ferritin light chain concentrations increase with age, whereas these are constant in the locus coeruleus; therefore iron could contribute to neurodegeneration in the substantia nigra more than in the locus coeruleus.5,6”

What the sources say

• Not checked yetcites [5] Zecca, 2001, Iron, Neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes, J Neurochem source
• Not checked yetcites [6] Zecca, 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging, Proc Natl Acad Sci USA source

In the paper

“In healthy individuals, total iron concentration in the locus coeruleus remains stable throughout life and is lower than in the substantia nigra, in which there is a linear increase in total iron concentration with age.6,52”

What the sources say

• Not checked yetcites [6] Zecca, 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging, Proc Natl Acad Sci USA source
• Not checked yetcites [52] Zucca, 2006, Neuromelanin and iron in human locus coeruleus and substantia nigra during aging: consequences for neuronal vulnerability, J Neural Transm source

In the paper

“Regional heterogeneity of brain iron and its change with age have both been confirmed in vivo by MRI.48–51”

What the sources say

• Not checked yetcites [48] Bartzokis, 2007, Brain ferritin iron may influence age- and gender-related risks of neurodegeneration, Neurobiol Aging source
• Not checked yetcites [49] Aquino, 2009, Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects, Radiology source
• Not checked yetcites [50] Bartzokis, 2011, Gender and iron genes may modify associations between brain iron and memory in healthy aging, Neuropsychopharmacology source
• Not checked yetcites [51] Bilgic, 2012, MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping, Neuroimage source

In the paper

“Little is known about iron metabolism in microglia but, in the course of microglial activation, iron uptake is thought to increase and iron exportation is down-regulated.31,32”

What the sources say

• Not checked yetcites [31] Crichton, 2006
• Not checked yetcites [32] Rathore, 2012, Iron homeostasis in astrocytes and microglia is differentially regulated by TNF-α and TGF-β1, Glia source

In the paper

“After 6 h, secreted hepcidin provoked a decrease of ferroportin in astrocytes, microglia, and neurons and an increase in DMT1 in microglia.”

What the sources say

• Not checked yetcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source

In the paper

“This accumulation is associated with changes in the two iron transporters, DMT1 and ferroportin; stimulated hippocampal neurons showed substantial increases in DMT1 and decreased concentrations of ferroportin, whereas microglia showed increased DMT1 protein concentrations but no changes in ferroportin.”

What the sources say

• Not checked yetcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source

In the paper

“Regional distribution of total iron in a healthy adult brain is heterogeneous; the highest iron concentrations were detected in the basal ganglia (putamen, globus pallidus, and caudate nucleus), whereas low concentrations were detected in the cortical grey matter, white matter, midbrain, and cerebellum, and the lowest iron concentrations were in the pons, locus coeruleus, and medulla.6,43,45–47”

What the sources say

• Not checked yetcites [6] Zecca, 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging, Proc Natl Acad Sci USA source
• Not checked yetcites [43] Ramos, 2014, Iron levels in the human brain: a post-mortem study of anatomical region differences and age-related changes, J Trace Elem Med Biol source
• Not checked yetcites [45] Zecca, 1996, Interaction of Neuromelanin and iron in substantia nigra and other areas of human brain, Neuroscience source
• Not checked yetcites [46] Zecca, 2001, The determination of iron and other metals by INAA in cortex, cerebellum and putamen of human brain and in their neuromelanins, J Radioanal Nucl Chem source
• Not checked yetcites [47] House, 2012, Aluminium, iron and copper in human brain tissues donated to the Medical Research Council's Cognitive Function and Ageing Study, Metallomics source

In the paper

“Iron is mostly found as ferritin and transferrin in oligodendrocytes,28,33 whereas, in astrocytes and microglia the iron form remains undefined.29”

What the sources say

• Not checked yetcites [28] Connor, 1990, Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains, J Neurosci Res source
• Not checked yetcites [33] Connor, 1995, Cellular management of iron in the brain, J Neurol Sci source
• Not checked yetcites [29] Badaracco, 2010, Oligodendrogenesis: the role of iron, Biofactors source

In the paper

“There is an increased pro-inflammatory state in the brains of the elderly. Glial cell numbers increase in the normal ageing brain, and there is increased immunoreactivity of astrocytic and microglial markers.”

What the sources say

• Not checked yetcites [37] Conde, 2006, Microglia in the aging brain, J Neuropathol Exp Neurol source
• Not checked yetcites [38] Farrall, 2009, Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis, Neurobiol Aging source
• Not checked yetcites [54] Block, 2007, Microglia-mediated neurotoxicity: uncovering the molecular mechanisms, Nat Rev Neurosci source

In the paper

“During neuroinflammation, glial cells are activated, which perturbs iron homoeostasis.34,35”

What the sources say

• Not checked yetcites [34] Lee, 2004, The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes, Proc Natl Acad Sci USA source
• Not checked yetcites [35] Nemeth, 2004, IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin, J Clin Invest source

In the paper

“In the elderly brain, there is a subpopulation of ferritin-positive microglia cells and most of these cells have aberrant dystrophic-type morphology.”

What the sources say

• Not checked yetcites [55] Lopes, 2008, Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity, Glia source

In the paper

“Although haem oxygenase 1 (HO-1) is considered to be cytoprotective, up-regulation of this enzyme in glia might contribute to neurodegeneration: as brains age, the prolonged action of HO-1 in astrocytes is likely to be involved in iron sequestration, intracellular oxidative stress, and mitochondrial insufficiency.56”

What the sources say

• Not checked yetcites [56] Schipper, 2009, Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement, J Neurochem source

In the paper

“Neurodegeneration that results from iron toxicity can lead to apoptosis73 and ferroptosis, an iron-specific form of non-apoptotic cell death.74”

What the sources say

• Not checked yetcites [73] Ott, 2007, Mitochondria, oxidative stress and cell death, Apoptosis source
• Not checked yetcites [74] Dixon, 2012, Ferroptosis: an iron-dependent form of nonapoptotic cell death, Cell source

In the paper

“ROS can damage DNA and mtDNA,58 affect DNA expression by epigenetic mechanisms,59 and oxidise proteins.”

What the sources say

• Not checked yetcites [58] Melis, 2013, Oxidative DNA damage and nucleotide excision repair, Antioxid Redox Signal source
• Not checked yetcites [59] Kwok, 2010, Role of epigenetics in Alzheimer's and Parkinson's disease, Epigenomics source

In the paper

“Oligodendrocytes contain the largest amount of iron, stored mainly as ferritin and transferrin, and concentration remains constant as people age.28”

What the sources say

• Not checked yetcites [28] Connor, 1990, Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains, J Neurosci Res source

In the paper

“Inclusion bodies containing damaged or aggregated proteins could cause endoplasmic reticulum stress, which is a common feature of several neurodegenerative diseases.72”

What the sources say

• Not checked yetcites [72] Liu, 2012, Iron and ER stress in neurodegenerative disease, Biometals source

In the paper

“IRP binding to IRE might interfere with APP translation and translocation across the endoplasmic reticulum membrane; the interference could be substantial because α secretase activity needs membrane-bound APP.81”

What the sources say

• Not checked yetcites [81] Rogers, 2002, An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript, J Biol Chem source

In the paper

“Microtubule-associated protein tau (MAPT) deficiency induces intracellular iron accumulation, which causes degeneration of dopaminergic neurons, leading to parkinsonism with dementia in mice.85”

What the sources say

• Not checked yetcites [85] Lei, 2012, Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export, Nat Med source

In the paper

“By contrast, iron deficiency will increase furin activity, thereby enhancing α secretase and stimulating the non-amyloidogenic pathway.78,80”

What the sources say

• Not checked yetcites [78] Altamura, 2009, Iron toxicity in diseases of aging: Alzheimer's disease, Parkinson's disease and atherosclerosis, J Alzheimers Dis source
• Not checked yetcites [80] Silvestri, 2008, A potential pathogenetic role of iron in Alzheimer's disease, J Cell Mol Med source

In the paper

“Increased iron concentrations accompany Aβ aggregation in areas initially affected in Alzheimer’s disease and offer an opportunity for a MRI-based diagnosis.”

What the sources say

• Not checked yetcites [86] Schenck, 2003, Magnetic resonance imaging of brain iron, J Neurol Sci source
• Not checked yetcites [87] Haacke, 2005, Imaging iron stores in the brain using magnetic resonance imaging, Magn Reson Imaging source

In the paper

“APP was suggested to have ferroxidase activity,82 but this has not been confirmed by in-vitro studies with a peptide containing the iron-binding REXXE motif and the full-length protein.83,84”

What the sources say

• Not checked yetcites [82] Duce, 2010, Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease, Cell source
• Not checked yetcites [83] Ebrahimi, 2012, A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP) does not catalytically oxidize iron, PLoS One source
• Not checked yetcites [84] Honarmand Ebrahimi, 2013, The amyloid precursor protein (APP) does not have a ferroxidase site in its E2 domain, PLoS One source

In the paper

“Abnormal homoeostasis of zinc, copper, and iron metal ions has been implicated in the misfolding process associated with the production of amyloid β (Aβ), from amyloid precursor protein (APP), hyperphosphorylated tau (found in the plaques and tangles), and contributing to neuronal oxidative stress.76”

What the sources say

• Not checked yetcites [76] Sayre, 2000, In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals, J Neurochem source

In the paper

“Excessive amounts of total iron will decrease furin activity because transcription of furin is modulated by cellular concentrations of iron, leading to decreased furin protein concentrations which thereby favours β secretase activity and enhances the amyloidogenic pathway.”

What the sources say

• Not checked yetcites [78] Altamura, 2009, Iron toxicity in diseases of aging: Alzheimer's disease, Parkinson's disease and atherosclerosis, J Alzheimers Dis source
• Not checked yetcites [80] Silvestri, 2008, A potential pathogenetic role of iron in Alzheimer's disease, J Cell Mol Med source

In the paper

“Although MRI resolution is not sufficient to detect individual plaques, T2* abnormalities that result from plaque aggregates might be detected with MRI.”

What the sources say

• Not checked yetcites [88] Jack, 2005, In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer's transgenic mice, J Neurosci source
• Not checked yetcites [89] Nabuurs, 2011, High-field MRI of single histological slices using an inductively coupled, self-resonant microcoil: application to ex vivo samples of patients with Alzheimer's disease, NMR Biomed source
• Not checked yetcites [90] Antharam, 2012, High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: quantitative imaging and correlation with iron, Neuroimage source

In the paper

“Increased redox-active iron is higher in patients with the most severe neuronal loss and is absent in neurons without neuromelanin.122–124”

What the sources say

• Not checked yetcites [122] Jellinger, 1992, Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis, J Neurochem source
• Not checked yetcites [123] Good, 1992, Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study, Brain Res source
• Not checked yetcites [124] Faucheux, 2003, Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease, J Neurochem source

In the paper

“Iron deposits in presenilin/APP transgenic mice models of Alzheimer’s disease93 colocalise with Aβ plaques,94,95 and increases in total brain iron coincide with early plaque formation.96”

What the sources say

• Not checked yetcites [93] Holcomb, 1998, Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes, Nat Med source
• Not checked yetcites [94] Smith, 1998, Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress, J Neurochem source
• Not checked yetcites [95] Falangola, 2005, Histological co-localization of iron in Abeta plaques of PS/APP transgenic mice, Neurochem Res source
• Not checked yetcites [96] Leskovjan, 2011, Increased brain iron coincides with early plaque formation in a mouse model of Alzheimer's disease, Neuroimage source

In the paper

“In patients with Parkinson’s disease, semi-quantitative histochemical methods showed that iron deposits were present in the neurons and glia of the substantia nigra, putamen, and globus pallidus, with an increase of ferritin-loaded microglia cells in the substantia nigra.112”

What the sources say

• Not checked yetcites [112] Jellinger, 1990, Brain iron and ferritin in Parkinson's and Alzheimer's diseases, J Neural Transm Park Dis Dement Sect source

In the paper

“Investigations have shown an increase in redox-active iron associated with neuromelanin in substantia nigra neurons of patients with Parkinson’s disease, probably as a result of decreased ferritin synthesis.”

What the sources say

• Not checked yetcites [122] Jellinger, 1992, Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis, J Neurochem source
• Not checked yetcites [123] Good, 1992, Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study, Brain Res source
• Not checked yetcites [124] Faucheux, 2003, Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease, J Neurochem source

In the paper

“HO-1 is up-regulated in the hippocampus and temporal cortex of patients with Alzheimer’s disease or mild cognitive impairment, which further implicates this haem-degrading enzyme in the pathogenesis of Alzheimer’s disease.98,99”

What the sources say

• Not checked yetcites [98] Schipper, 1995, Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain, Ann Neurol source
• Not checked yetcites [99] Schipper, 2006, Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment, Neurobiol Aging source

In the paper

“In-vitro and in-vivo studies have confirmed the ability of neuromelanin to activate microglia and induce death of dopamine neurons.127,128”

What the sources say

• Not checked yetcites [127] Zecca, 2008, Human Neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease, Acta Neuropathol source
• Not checked yetcites [128] Zhang, 2011, Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson's disease, Neurotox Res source

In the paper

“High concentrations of iron detected in the substantia nigra of individuals with Parkinson’s disease might exceed the iron-buffering capacity of complexes, such as neuromelanin and ferritin, and could induce neurotoxicity.124”

What the sources say

• Not checked yetcites [124] Faucheux, 2003, Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease, J Neurochem source

In the paper

“A contributing factor to the increased iron accumulation in Parkinson’s disease might be increased DMT1 activity or decreased ferroxidase activity of ceruloplasmin, both of which would increase total intracellular iron, as reported in an animal model of Parkinson’s disease109 and in patients.131–134”

What the sources say

• Not checked yetcites [109] Salazar, 2008, Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease, Proc Natl Acad Sci USA source
• Not checked yetcites [131] Boll, 1999, Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease, Neurosci Lett source
• Not checked yetcites [132] Boll, 2008, Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases, Neurochem Res source
• Not checked yetcites [133] Martínez-Hernández, 2011, Plasma ceruloplasmin ferroxidase activity correlates with the nigral sonographic area in Parkinson's disease patients: a pilot study, Neurochem Res source
• Not checked yetcites [134] Olivieri, 2011, Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention, J Neurosci source

In the paper

“Reduced ferroxidase activity of ceruloplasmin was noted in the CSF of patients with Parkinson’s disease together with increased CSF copper concentrations by comparison with controls,131 a condition which could contribute to the increased mobilisation of reactive iron and oxidative stress reported in Parkinson’s disease.”

What the sources say

• Not checked yetcites [131] Boll, 1999, Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease, Neurosci Lett source

In the paper

“MRI measures generally have been found to correlate with disability and thus might be used to monitor disease progression.104,144,145”

What the sources say

• Not checked yetcites [104] Péran, 2010, Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature, Brain source
• Not checked yetcites [144] Gorell, 1995, Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease, Neurology source
• Not checked yetcites [145] Martin, 2008, Midbrain iron content in early Parkinson disease: a potential biomarker of disease status, Neurology source

In the paper

“This increased risk is likely to be due to the need for adequate supplies of iron for the synthesis of neurotransmitters, such as dopamine, because iron is a cofactor of tyrosine hydroxylase (the key enzyme of dopamine synthesis).”

In the paper

“Despite the aforementioned increases of total and reactive iron content in brain areas of patients with Parkinson’s disease, increased concentrations of total serum iron are causally associated with a decreased risk of developing Parkinson’s disease, thus showing a potentially protective effect of peripheral iron.138,139”

What the sources say

• Not checked yetcites [138] Pichler, 2013, Serum iron levels and the risk of Parkinson disease: a mendelian randomization study, PLoS Med source
• Not checked yetcites [139] Miyake, 2011, Dietary intake of metals and risk of Parkinson's disease: a case-control study in Japan, J Neurol Sci source

In the paper

“Transcranial sonography might be a helpful technique in the diagnosis of Parkinson’s disease, Friedreich’s ataxia, Huntington’s disease, and restless leg syndrome and might be useful to differentiate between idiopathic Parkinson’s disease and atypical parkinsonian syndromes.152”

What the sources say

• Not checked yetcites [152] Bouwmans, 2010, Transcranial sonography for the discrimination of idiopathic Parkinson's disease from the atypical parkinsonian syndromes, Int Rev Neurobiol source

In the paper

“In Parkinson’s disease, loss of neuromelanin and an increase in iron concentration is noted in the substantia nigra.”

What the sources say

• Not checked yetcites [153] Zecca, 2005, In vivo detection of iron and Neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage, Mov Disord source

In the paper

“Overexpression of DMT1 and iron accumulation was noted in the mesencephalon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine animal models of Parkinson’s disease.109”

What the sources say

• Not checked yetcites [109] Salazar, 2008, Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease, Proc Natl Acad Sci USA source

In the paper

“A positive association between iron and ferritin concentrations, and a negative association of neuromelanin content with the area of echogenicity of the substantia nigra could therefore provide a basis for diagnosis and therapeutic follow-up studies in patients with Parkinson’s disease.153”

What the sources say

• Not checked yetcites [153] Zecca, 2005, In vivo detection of iron and Neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage, Mov Disord source

In the paper

“Ultrasound investigation of post-mortem brains from healthy individuals showed a positive correlation between the echogenic area of the substantia nigra and concentration of iron and heavy and light chain ferritin, and a negative correlation between echogenicity and neuromelanin content of the substantia nigra.”

What the sources say

• Not checked yetcites [153] Zecca, 2005, In vivo detection of iron and Neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage, Mov Disord source

In the paper

“Preliminary reports state that identification of neuromelanin (rather than iron) by MRI might be feasible in patients with Parkinson’s disease.148,149”

What the sources say

• Not checked yetcites [148] Nakane, 2008, Visualization of neuromelanin in the substantia nigra and locus ceruleus at 1·5T using a 3D-gradient echo sequence with magnetization transfer contrast, Magn Reson Med Sci source
• Not checked yetcites [149] Sasaki, 2008, Neuromelanin-sensitive MRI. Basics, technique and clinical applications, Clin Neuroradiol source

In the paper

“Increased amounts of iron were assayed in the brains of both the 6-hydroxydopamine and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine animal model of Parkinson’s disease,109,154 consistent with the increased expression of a DMT1 isoform (+IRE) reported in the substantia nigra of patients with Parkinson’s disease.”

What the sources say

• Not checked yetcites [109] Salazar, 2008, Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease, Proc Natl Acad Sci USA source
• Not checked yetcites [154] Song, 2010, Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson's disease, Free Radic Biol Med source

In the paper

“frataxin probably regulates iron handling in mitochondria, and prevents iron from generating oxidative stress.”

What the sources say

• Not checked yetcites [57] Crichton, 2014

In the paper

“PBT2 binds excesses of copper and zinc and possibly iron in the brain, thereby diminishing the amount of amyloid plaque formation and relocating these metal ions to depleted cellular and neuronal compartments.218”

What the sources say

• Not checked yetcites [218] Crouch, 2011, The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity, J Neurochem source