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A Quantitative Analysis of Isoferritins in Select Regions of Aged, Parkinsonian, and Alzheimer's Diseased Brains
Abstract
Abstract: The brain requires a ready supply of iron for normal neurological function, but free iron is toxic. Consequently, iron bioavailability must be stringently regulated. Recent evidence has suggested that the brain iron regulatory system is dysfunctional in neurological disorders such as Alzheimer's and Parkinson's diseases (AD and PD, respectively). A key component of the iron regulatory system in the brain is ferritin. Ferritin consists of 24 subunits, which are distinguished as either a heavy‐chain (H) or light‐chain (L) isoform. These peptide subunits are genetically and functionally distinct. Thus, the ability to investigate separately the types of ferritin in brain should provide insight into iron management at both the cellular and the molecular level. In this study, the ratio of isoferritins was determined in select regions of adult elderly AD and PD human brains. The H‐rich ferritin was more abundant in the young brain, except in the globus pallidus where the ratio of H/L ferritin was 1:1. The balance of H/L isoferritins was influenced by age, brain region, and disease state. With normal aging, both H and L ferritin increased; however, the age‐associated increase in isoferritins generally failed to occur in AD and PD brain tissue. The imbalance in H/L isoferritins was disease and region specific. For example, in frontal cortex, there was a dramatic (fivefold) increase in the ratio of H/L ferritin in AD brains but not in PD brains. In PD, caudate and putamen H/L ratios were higher than in AD and the elderly control group. The analysis of isoferritin expression in brain provides insight into regional iron regulation under normal conditions and suggests a loss of ability to maintain iron homeostasis in the two disease states. This latter observation provides further evidence of dysfunction of iron homeostatic mechanisms in AD and PD and may contribute significantly to understanding the underlying pathogenesis of each, particularly in relation to iron‐induced oxidative damage.
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“Increases of iron and a decrease of ferritin in the substantia nigra101,116–119 are indicative of high iron loading of ferritin.120”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [119]
In the citing paper
“Moreover, low iron concentrations can reduce the neuronal deposits of ferritin, generating a condition in the substantia nigra neurons of patients with Parkinson’s disease.117,119”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [119]
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Self-citationOxidation-induced ferritin turnover in microglial cells: role of proteasome
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Self-citationPreserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration
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“The Aβ plaques contain a fairly large amount of labile iron, while the neighboring cells express significant levels of ferritin and transferrin receptors (Connor et al., 1995).”
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“Concentration of iron-binding proteins increases with age in the frontal white matter, basal ganglia, and substantia nigra (Bartzokis et al., 2007; Connor et al., 1995; Zecca et al., 2001).”
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Xu, J., Marzetti, E., Seo, A. Y., Kim, J., Prolla, T. A., & Leeuwenburgh, C. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.04.007 · Cited by 77
“In addition to these observations, studies in post-mortem brains showed an agedependent accumulation of ferritin, indicative of increased storage iron, in different brain regions (Thomas et al., 1993; Connor et al., 1995; Zecca et al., 2001).”
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“This potentially leads to iron storage deficiency, which allows unbound reactive iron to accumulate in the substantia nigra, facilitating ROS production (White and Munro, 1988; Dexter et al., 1991; Connor et al., 1995).”
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The Neuromelanin Paradox and Its Dual Role in Oxidative Stress and Neurodegeneration
Moreno-García, A., Kun, A., Calero, M., & Calero, O. (2021) · Antioxidants · doi:10.3390/antiox10010124 · Cited by 66
Neuroferritinopathy: From ferritin structure modification to pathogenetic mechanism
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“There have been varying reports concerning a possible cellular imbalance of the iron: ferritin ratio (Connor et al., 1992b, 1995; Dedman et al., 1992; Piñero et al., 2000), and also on the levels and activity of the important ferroxidase, ceruloplasmin (Castellani et al., 1999; Connor et al., 1993;…”
Baksi, S., Tripathi, A. K., & Singh, N. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.06.025 · Cited by 64
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“More recent postmortem studies have shown higher ferritin levels at older age in basal ganglia [17, 18].”
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“Hill and Switzer (1984) demonstrated that physiological iron accumulation occurs in the CNS almost exclusively in OLs and thus OLs stained for iron more robustly that any other cell in the normal adult brain (Benkovic and Connor, 1993; Connor and Menzies, 1995; Connor et al., 1995).”
BackgroundIron Pathophysiology in Alzheimer’s Diseases
Wang, T., Xu, S.-F., Fan, Y.-G., Li, L.-B., & Guo, C. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-9589-5_5 · Cited by 64
Ferroptosis in Parkinson's disease —— The iron-related degenerative disease
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“by the Meguro method and ferritin IHC is possibly caused by binding of iron to some of the many molecules other than ferritin in the extracellular compartment of plaques (Grundke-Iqbal et al. 1990; Connor et al. 1995).”
MethodSaini, N., Oelhafen, S., Hua, H., Georgiev, O., Schaffner, W., & Büeler, H. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.05.011 · Cited by 63
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“In PD patients there is a decrease of brain Light chain-ferritin as compared to controls [16].”
BackgroundDopaminergic cell death precedes iron elevation in MPTP-injected monkeys
He, Y., Thong, P. S. P., Lee, T. T., Leong, S. K., Mao, B. Y., Dong, F., & Watt, F. (2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(03)00385-x · Cited by 62
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“The difference between the results obtained by these authors and also by us and those cited earlier [17], might be due to the different methods used, as our study and that by Zecca et al.”
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Evaluation of HFE (hemochromatosis) mutations as genetic modifiers in sporadic AD and MCI
Berlin, D., Chong, G., Chertkow, H. M., Bergman, H., Phillips, N. A., & Schipper, H. M. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.06.008 · Cited by 58
“Attempts to delineate metabolic pathways subserving the enhanced sequestration of iron in AD brain have revealed aberrations in the CNS expression of proteins implicated in iron mobilization and storage, including transferrin receptor [13], ferritin [4], iron response proteins [21], lactoferrin [14], melanotransferrin…”
BackgroundFerroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases
Zhou, J.-P., Jin, Y., Lei, Y.-H., Liu, T., Wan, Z., Meng, H., & Wang, H. (2020) · Neurodegenerative Diseases · doi:10.1159/000510083 · Cited by 57
Mechanisms of Neurodegeneration in Various Forms of Parkinsonism—Similarities and Differences
Koziorowski, D., Figura, M., Milanowski, Ł., Szlufik, S., Alster, P., Madetko‐Alster, N., & Friedman, A. (2021) · Cells · doi:10.3390/cells10030656 · Cited by 59
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Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease
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“Similarly, a loss of association has been also reported between ferritin H and L subunits in AD [44], indicating the complexity of the AD pathology.”
BackgroundInfluentialIron stored in ferritin is chemically reduced in the presence of aggregating Aβ(1-42)
Everett, J. L., Brooks, J., Lermyte, F., O’Connor, P. B., Sadler, P. J., Dobson, J., Collingwood, J. F., & Telling, N. D. (2020) · Scientific Reports · doi:10.1038/s41598-020-67117-z · Cited by 57
Reversion of age-related recognition memory impairment by iron chelation in rats
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Regulatory mechanisms for iron transport across the blood-brain barrier
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Identification of L-ferritin in Neuromelanin Granules of the Human Substantia Nigra
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Redox Metals in Alzheimer's Disease
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“In both Parkinson’s disease and Alzheimer’s disease the normal age-associated increase in the expression of ferritin and the expected change in the H-subunit/L-subunit ratio fail to occur (Connor et al., 1995; Dexter et al., 1992; Faucheux et al., 2002).”
BackgroundInfluentialBrain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells
Garrido‐Gil, P., Rodríguez‐Pallares, J., Dominguez‐Meijide, A., Guerra, M. J., & Labandeira-García, J. L. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.10.013 · Cited by 51
Overdosing on iron: Elevated iron and degenerative brain disorders
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“Postmortem biochemical studies have measured elevated total iron concentrations in the AD brain (4–8), but interestingly ferritin, the protein that stores iron in a nonreactive oxidized form, appears to be lower in cortical brain regions more severely affected by the disease (9).”
BackgroundSources and mechanisms of cytoplasmic oxidative damage in Alzheimer's disease
Marlatt, M. W., Lee, H., Perry, G. L., Smith, M. A., & Zhu, X. (2004) · Acta Neurobiologiae Experimentalis · doi:10.55782/ane-2004-1493 · Cited by 49
“crease in ferritin, which would leave the neurons vulnerable to ROS since there is apparently not enough ferritin to detoxify iron, is seen in AD brain (Connor et al. 1995).”
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“…redox-active labile iron in PD is compounded by a loss of the buffering capacity of iron storage proteins; neurome-lanin (Faucheux et al., 2003) and Ft (Connor et al., 1995) as well as iron-catalyzed aggregation of α -synuclein to form bodies in surviving neurons (Lotharius and Brundin, 2002).”
BackgroundIron overload triggers redox-sensitive signals in human IMR-32 neuroblastoma cells
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“The linkage between iron and ferritin in brain, but not in liver, is suggestive of different regulatory approaches and is consistent with a much greater prevalence of H ferritin in brain than in liver (16).”
BackgroundRole of Iron in the Molecular Pathogenesis of Diseases and Therapeutic Opportunities
Abbasi, U., Abbina, S., Gill, A., Takuechi, L. E., & Kizhakkedathu, J. N. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00122 · Cited by 48
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“It has been reported that L-ferritin is decreased in PD brains compared to controls (Connor et al., 1995; Koziorowski et al., 2007).”
BackgroundNitric Oxide Protects Astrocytes from Oxidative Stress
Robb, S. J., & Connor, J. R. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04059.x · Cited by 45
Self-citationIron in Alzheimer’s Disease: From Physiology to Disease Disabilities
Pal, A., Cerchiaro, G., Rani, I., Ventriglia, M., Rongioletti, M. C. A., Longobardi, A., & Squitti, R. (2022) · Biomolecules · doi:10.3390/biom12091248 · Cited by 49
Peripheral iron dextran induced degeneration of dopaminergic neurons in rat substantia nigra
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Iron as a cause of Parkinson disease – a myth or a well established hypothesis?
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“A decrease of the concentration of L ferritin in parkinsonian SN was found several years ago [24].”
BackgroundDesferoxamine reverses neonatal iron-induced recognition memory impairment in rats
de Lima, M. N. M., Presti-Torres, J., Caldana, F., Grazziotin, M. M., Scalco, F. S., Guimarães, M. R., Bromberg, E., Franke, S. I. R., Henriques, J. A. P., & Schröder, N. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.06.002 · Cited by 43
“Although it is known that iron uptake by the brain is higher during the development of the nervous system, there is a continuous iron uptake resulting in iron accumulation during the aging process (Connor et al., 1990; Connor et al., 1995).”
BackgroundDonovan, L. E., Dammer, E. B., Duong, D. M., Hanfelt, J., Levey, A. I., Seyfried, N. T., & Lah, J. J. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt186 · Cited by 43
“Ferritin heavy and light chains, usually found in a 1:1 stoichiometry, increase with age in normal, but not AD brain, and a distinguishing feature of frontal cortex in AD compared to Parkinson’s disease was a large, 5-fold, increase in heavy/light ferritin ratio [69].”
BackgroundHFE gene variants, iron, and lipids: a novel connection in Alzheimer’s disease
Ali-Rahmani, F. G., Schengrund, C., & Connor, J. R. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00165 · Cited by 43
Self-citationFerritin oxidation and proteasomal degradation: Protection by antioxidants
Voß, P., Horáková, Ľ., Jakstadt, M., Kiekebusch, D., & Grune, T. (2006) · Free Radical Research · doi:10.1080/10715760500419357 · Cited by 41
“Furthermore, the content of ferritin in specific regions of the brain is altered during aging or Alzheimer’s and Parkinson’s disease [10,49,50].”
BackgroundOxidative stress in the aging murine olfactory bulb: Redox proteomics and cellular localization
Vaishnav, R., Getchell, M. L., Poon, H. F., Barnett, K. R., Hunter, S. A., Pierce, W. M. J., Klein, J. B., Butterfield, D. A., & Getchell, T. V. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.21130 · Cited by 42
“The expression of FTH, an oxidative stress-response protein that plays a key role in iron homeostasis, was significantly increased in the OBs of old mice (Poon et al., 2005), consistent with its increase in other brain regions with aging (Connor et al., 1995; Zecca et al., 2004).”
BackgroundZhang, N., Yu, X., Song, L., Xiao, Z., Xie, J., & Xu, H. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.11.018 · Cited by 41
A novel approach to quantify different iron forms in ex-vivo human brain tissue
Kumar, P., Bulk, M., WEBB, A. G., van der Weerd, L., Oosterkamp, T. H., Huber, M., & Bossoni, L. (2016) · Scientific Reports · doi:10.1038/srep38916 · Cited by 40
Regulating amyloid precursor protein synthesis through an internal ribosomal entry site
Beaudoin, M. E., Poirel, V., & Krushel, L. A. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn792 · Cited by 40
“However, in AD patients, there is a further enrichment of iron in the brain without the concomitant increase in ferritin (29,30).”
BackgroundExpression of ferritin protein and subunit mRNAs in normal and iron deficient rat brain
Hansen, T. M., Nielsen, H., Bernth, N., et al. (1999) · Molecular Brain Research · doi:10.1016/s0169-328x(99)00011-x · Cited by 39
Blood donations, iron stores, and risk of Parkinson's disease
Logroscino, G., Chen, H., Wing, A., & Ascherio, A. (2006) · Movement Disorders · doi:10.1002/mds.20826 · Cited by 38
Amit, T., Bar‐Am, O., Mechlovich, D., Kupershmidt, L., Youdim, M. B. H., & Weinreb, O. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.05.026 · Cited by 38
“various brain regions (Connor et al., 1995) (Zecca et al.”
BackgroundCozzi, A., Santambrogio, P., Corsi, B., Campanella, A., Arosio, P., & Levi, S. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.05.004 · Cited by 38
Self-citationFerritin levels in microglia depend upon activation: Modulation by reactive oxygen species
Mehlhase, J., Gieche, J., Widmer, R., & Grune, T. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.04.012 · Cited by 38
Kaur, D., Rajagopalan, S., Chinta, S., Kumar, J., Di Monte, D., Cherny, R. A., & Andersen, J. K. (2007) · Brain Research · doi:10.1016/j.brainres.2006.03.006 · Cited by 36
Waugh, W. H. (2008) · Gerontology · doi:10.1159/000122618 · Cited by 36
“in 1953 and is supported strongly by the studies of Connor et al. [”
ResultMeng, F. X., Hou, J. M., & Sun, T. (2017) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-017-0578-z · Cited by 36
“Fn can be of the H or L type [46, 47]; the former is involved in the rapid uptake and reuse of iron, while the latter is associated with long-term iron storage [48].”
BackgroundGetting the iron out: Phlebotomy for Alzheimer’s disease?
Dwyer, B. E., Zacharski, L. R., Balestra, D. J., Lerner, A. J., Perry, G. L., Zhu, X., & Smith, M. A. (2009) · Medical Hypotheses · doi:10.1016/j.mehy.2008.12.029 · Cited by 35
“Intracellular iron storage in ferritin could be impaired in AD brain [57–60].”
BackgroundIron and Targeted Iron Therapy in Alzheimer’s Disease
Wang, J., Fu, J., Zhao, Y., Liu, Q., Yan, X., & Su, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216353 · Cited by 35
“In contrast, FTL is associated with long-term iron storage and present in tissues with storage functions and low iron oxidation activity (e.g., the spleen, liver, and placenta) [27].”
BackgroundThe history of the research of iron in parkinsonian substantia nigra
Friedman, A., & Gałązka-Friedman, J. (2012) · Journal of Neural Transmission · doi:10.1007/s00702-012-0894-8 · Cited by 34
“It was found that in PD SN there is a substantial decrease in the concentration of L-chains of ferritin, compared to control (Connor et al. 1995; GalazkaFriedman et al. 2004).”
BackgroundWalker, T. A., Michaelides, C., Ekonomou, A., Geraki, K., Parkes, H. G., Suessmilch, M., Herlihy, A. H., Crum, W. R., & So, P. (2016) · Aging · doi:10.18632/aging.101069 · Cited by 36
Kupershmidt, L., & Youdim, M. B. H. (2023) · Cells · doi:10.3390/cells12050763 · Cited by 36
Transcranial Sonography in Brain Disorders with Trace Metal Accumulation
Walter, U. (2010) · International review of neurobiology · doi:10.1016/s0074-7742(10)90012-3 · Cited by 34
Metal attenuating therapies in neurodegenerative disease
Mot, A. I., Wedd, A. G., Sinclair, L., Brown, D. R., Collins, S. J., & Brazier, M. W. (2011) · Expert Review of Neurotherapeutics · doi:10.1586/ern.11.170 · Cited by 32
Matching ex vivo MRI With Iron Histology: Pearls and Pitfalls
De Barros, A., Arribarat, G., Combis, J., Chaynes, P., & Péran, P. (2019) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2019.00068 · Cited by 31
“The H/L ratio increases with age by a factor 2–3 (Connor et al., 1995).”
BackgroundAltered regulation of iron transport and storage in Parkinson’s disease
Hirsch, É. C. (2006) · Springer eBooks · doi:10.1007/978-3-211-33328-0_21 · Cited by 30
“MPTP-intoxicated monkeys (Dexter et al., 1991; Mann et al., 1994; Connor et al., 1995; Goto et al., 1996).”
ResultHe, Y., Lee, T., & Leong, S. K. (1999) · Free Radical Research · doi:10.1080/10715769900301611 · Cited by 30
Svobodová, H., Kosnáč, D., Balázsiová, Z., Tanila, H., Miettinen, P. O., Sierra, A., Vitovič, P., Wagner, A., Polák, Š., & Kopáni, M. (2019) · Physiological Research · doi:10.33549/physiolres.934383 · Cited by 28
Magnetic resonance relaxometry in Parkinson's disease
Mondino, F., Filippi, P., Magliola, U., et al. (2002) · Neurological Sciences · doi:10.1007/s100720200083 · Cited by 29
“More recently, no increase in neuronal isoferritin was detected when specific brain isoforms of ferritin were evaluated [4].”
BackgroundCritical role of iron in the pathogenesis of the murine gangliosidoses
Jeyakumar, M., Williams, I. M., Smith, D. A. B., Cox, T. M., & Platt, F. M. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.01.015 · Cited by 29
Brain iron deposition in white matter hyperintensities: a 3-T MRI study
Yan, S., Sun, J., Chen, Y., Selim, M. H., & Lou, M. (2012) · AGE · doi:10.1007/s11357-012-9487-6 · Cited by 28
“Iron is present in high concentrations within the oligodendrocytes and myelin (Dwork et al. 1988; Francois et al. 1981; LeVine and Macklin 1990) and is associated with the biosynthetic enzymes of myelinogenesis (Connor et al. 1995).”
Magnetic Resonance Imaging Based Clinical Research in Alzheimer's Disease
Fayed, N. M., Modrego, P. J., Salinas, G. R., & Gazulla, J. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111292 · Cited by 29
Meng, F. X., Hou, J. M., & Sun, T. (2017) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-017-0526-y · Cited by 28
“The structure of Fn includes H and L subunits, of which the L subunit is associated with longterm iron storage [50, 51].”
Background
Metadata
- Authors
- Connor, J. R., Snyder, B. S., Arosio, P., Loeffler, D. A., & LeWitt, P.
- Affiliations
- Pennsylvania State University (US)
- University of Brescia (IT)
- Corresponding author
- Connor, James R.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1995-08
- Volume
- 65
- Issue
- 2
- Pages
- 717-724
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2078549368
- Cited by
- 317
- References
- 0
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 13 · 2021: 11 · 2020: 7 · 2019: 8 · 2018: 7 · 2017: 9 · 2016: 16 · 2015: 6 · 2014: 10 · 2013: 13 · 2012: 10
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag009063-03)
- National Institute on Aging (AG09063)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- isoferritins, FTH1, ferritin light chain, brain iron homeostasis, Alzheimer's disease, Parkinson's disease, brain aging, globus pallidus, caudate and putamen, frontal cortex, oxidative damage
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Ferritins, Humans, Isomerism, Middle Aged, Parkinson Disease, Tissue Distribution
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