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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-citationMRI evaluation of brain iron in earlier- and later-onset Parkinson’s disease and normal subjects
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Self-citationIron uptake and transport across physiological barriers
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“Regulating iron uptake at the BBB is of great importance because too little or too much iron has been associated with various neurological diseases (Table 1) (Allen et al. 2001; Connor et al. 1995).”
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“Altered levels of ferritin proteins have been shown consistently in PD in a multitude of experiments [34-36].”
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“2005), but this is not necessarily linked to pathological alteration or dysfunction of the brain; a parallel increase of ferritins is actually observed in normal aging (connor et al. 1995) that should guarantee the safe storage and handling of the metal.”
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Piñero, D. J., Li, N., Connor, J. R., & Beard, J. L. (2000) · Journal of Nutrition · doi:10.1093/jn/130.2.254 · Cited by 163
Self-citationAbnormal localization of iron regulatory protein in Alzheimer’s disease
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“Tim-2, a ferritin receptor (Han et al., 2011), aids in oligodendrocyte iron uptake while non-Tf bound iron is taken up via DMT1. in the basal ganglia including the putamen, globus pallidus, and substantia nigra (Hallgren and Sourander, 1958; Connor et al., 1990, 1992, 1995).”
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Microglial degeneration in the aging brain - bad news for neurons?
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“Previous studies have reported that iron accumulates in the human CNS with normal aging (Hallgren and Sourander, 1958; Connor et al., 1995; Zecca et al., 2001).”
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Oxidative Imbalance in Alzheimer's Disease
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“Also, an increase in iron concentration with a concurrent decrease in ferritin is observed in AD brain ( 67 ,68).”
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“We should also mention some other biomarkers that could be interesting for further studies, including imaging purposes, like TSPO/PBR (translocator protein (18kDa)) also known as Mitochondrial Benzodiazepine Receptor (peripheral), thus supporting its current role as a putative imaging biomarker for AD [448,449,450,451…”
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Snyder, A. M., & Connor, J. R. (2008) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2008.08.005 · Cited by 138
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“Previous studies have shown that iron, ferritins and NM (Sofic et al., 1988; Dexter et al., 1989; Connor et al., 1995; Zecca et al., 2001, 2002a) undergo dramatic changes in PD and have suggested that age plays an important role in these changes.”
ResultIron in the Brain: An Important Contributor in Normal and Diseased States
Piñero, D. J., & Connor, J. R. (2000) · The Neuroscientist · doi:10.1177/107385840000600607 · Cited by 132
“Specifically, H ferritin and L ferritin levels are reportedly 75% and 37% of normal, respectively (43).”
BackgroundSelf-citationFerritin as an important player in neurodegeneration
Friedman, A., Arosio, P., Finazzi, D., Koziorowski, D., & Gałązka-Friedman, J. (2011) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2011.03.016 · Cited by 131
“[76] on whole SN, showed a considerable decrease of L ferritin in PD.”
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Self-citationEmerging and Dynamic Biomedical Uses of Ferritin
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“Typically, a concomitant increase in ferritin levels are paired with increased iron levels [119], attempting to ensure safe handling of this increase in iron.”
BackgroundSelf-citationInfluence of neurotoxins and oxidative stress on the onset and progression of Parkinson’s disease
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Role of iron in neurodegenerative diseases
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“Furthermore, ferritin and neuromelanin are reported to be decreased in the SN of PD patients (Dexter et al. 1990; Connor et al. 1995; Zecca et al. 2002).”
Association study between iron-related genes polymorphisms and Parkinson's disease
Borie, C., Gasparini, F., Verpillat, P., Bonnet, A.-M., Agid, Y., Hetet, G., Brice, A., Dürr, A., & Grandchamp, B. (2002) · Journal of Neurology · doi:10.1007/s00415-002-0704-6 · Cited by 123
“Abnormal expression of several iron-related genes including H- and L-ferritin subunits [4], lactoferrin [12], transferrin receptor [13] have been reported.”
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Mitochondrial iron metabolism and neurodegenerative diseases
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Werner coordination chemistry and neurodegeneration
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Gerlach, M., Double, K. L., Ben‐Shachar, D., Zecca, L., Youdim, M. B. H., & Riederer, P. F. (2003) · Neurotoxicity Research · doi:10.1007/bf03033371 · Cited by 112
Brain iron accumulation in aging and neurodegenerative disorders
Hagemeier, J., Geurts, J. J. G., & Zivadinov, R. (2012) · Expert Review of Neurotherapeutics · doi:10.1586/ern.12.128 · Cited by 114
Potential sources of increased iron in the substantia nigra of parkinsonian patients
Gerlach, M., Double, K. L., Youdim, M. B. H., & Riederer, P. F. (2006) · Springer eBooks · doi:10.1007/978-3-211-45295-0_21 · Cited by 111
“Normal ageing is reported to be accompanied by an up-regulation of ferritin expression for reasons that are unknown; in PD this normal up-regulation response appears to fail (Connor et al., 1995).”
BackgroundResultCahill, C. M., Lahiri, D. K., Huang, X., & Rogers, J. T. (2008) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2008.12.001 · Cited by 108
House, M. J., Pierre, T. G. S., Kowdley, K. V., Montine, T. J., Connor, J. R., Beard, J., Berger, J., Siddaiah, N. B., Shankland, E. G., & Jin, L. (2006) · Magnetic Resonance in Medicine · doi:10.1002/mrm.21118 · Cited by 103
“Although total iron appears to be elevated in several AD brain regions (1,7–10), both H- and L-ferritin levels are generally similar or significantly lower in AD basal ganglia and some cortical regions compared to ferritin levels in healthy controls (7,34).”
BackgroundSelf-citationAksenova, M. V., Aksenov, M. Y., Payne, R. M., Trojanowski, J. Q., Schmidt, M. L., Carney, J. M., Butterfield, D. A., & Markesbery, W. R. (1999) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000017098 · Cited by 105
Iron Metabolism in Aging and Age-Related Diseases
Tian, Y., Tian, Y., Yuan, Z., Zeng, Y., Wang, S., Fan, X., Yang, D., & Yang, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073612 · Cited by 110
“Young individuals had relatively high levels of heavy-chain (H) ferritin compared to light-chain (L) ferritin; However, H and L-ferritin in the frontal cortex, caudate nucleus, putamen, substantia nigra, and globus pallidus are increased with age [56].”
BackgroundInfluence of neuromelanin on oxidative pathways within the human substantia nigra
Double, K. L., Ben-Shachar, D., Youdim, M. B. H., Zecca, L., Riederer, P., & Gerlach, M. (2002) · Neurotoxicology and Teratology · doi:10.1016/s0892-0362(02)00218-0 · Cited by 102
The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System
Joppe, K., Roser, A., Maass, F., & Lingor, P. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00015 · Cited by 103
“In PD, reduced ferritin levels in SN and pathological iron accumulation were found (Dexter et al., 1991; Connor et al., 1995).”
BackgroundSignal Transduction Cascades Associated with Oxidative Stress in Alzheimer's Disease
Petersen, R. B., Nunomura, A., Lee, H., Casadesús, G., Perry, G. L., Smith, M. A., & Zhu, X. (2007) · Journal of Alzheimer s Disease · doi:10.3233/jad-2007-11202 · Cited by 101
Skjørringe, T., Møller, L. B., & Moos, T. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00169 · Cited by 104
“Also ferritin accumulation has been reported in some – but not all – Parkinson’s disease patients (Dexter et al., 1991; Connor et al., 1995; Faucheux et al., 2002; Bartzokis et al., 2004).”
BackgroundImpaired iron homeostasis in Parkinson’s disease
Double, K. L., Gerlach, M., Youdim, M. B. H., & Riederer, P. F. (2000) · Springer eBooks · doi:10.1007/978-3-7091-6301-6_3 · Cited by 101
Macroautophagy is impaired in old murine brain tissue as well as in senescent human fibroblasts
Ott, C., König, J., Höhn, A., Jung, T., & Grune, T. (2016) · Redox Biology · doi:10.1016/j.redox.2016.10.015 · Cited by 96
Dietary Iron Intake and Risk of Parkinson's Disease
Logroscino, G., Gao, X., Chen, H., Wing, A., & Ascherio, A. (2008) · American Journal of Epidemiology · doi:10.1093/aje/kwn273 · Cited by 93
Nakada, T., Matsuzawa, H., Igarashi, H., Fujii, Y., & Kwee, I. L. (2007) · Journal of Neuroimaging · doi:10.1111/j.1552-6569.2007.00179.x · Cited by 92
Li, X., Allen, R. P., Earley, C. J., Liu, H., Cruz, T. E., Edden, R. A. E., Barker, P. B., & van Zijl, P. C. M. (2016) · Sleep Medicine · doi:10.1016/j.sleep.2016.05.001 · Cited by 93
“H-ferritin has been shown to be more abundant than L-ferritin in the cortex and in most regions of the brain [67, 68], with a ratio of H/L isoferritins to be around 2 to 4 in the SN in elderly population [68, 69].”
BackgroundBook Review: Iron and Parkinson’s Disease
Wolozin, B. L., & Golts, N. (2002) · The Neuroscientist · doi:10.1177/107385840200800107 · Cited by 89
Review: Iron metabolism and the role of iron in neurodegenerative disorders
Hadzhieva, M., Kirches, E., & Mawrin, C. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12096 · Cited by 90
Copper and iron in Alzheimer's disease: a systematic review and its dietary implications
Loef, M., & Walach, H. (2011) · British Journal Of Nutrition · doi:10.1017/s000711451100376x · Cited by 87
“There is, moreover, a change in the protein level involved in the Fe homeostasis: ferritin, an intracellular Fe-storage-protein, is increased in microglia((111)) and senile plaques((112)) with a fivefold increase in the cortical ratio of its protein subunits, the heavy and the light chain((123)).”
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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