The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases
Abstract
:1. Introduction and Objectives of This Review
2. Alzheimer’s Disease
2.1. Iron Dysregulation in AD
2.2. Cellular Iron Dysregulation in AD
2.3. Hypothesis 1
2.3.1. Iron Accumulation Is a Consequence of Pathological Alterations Related to Aβ
2.3.2. Iron Accumulation Is a Consequence of Pathological Alterations in Tau
2.4. Hypothesis 2
2.4.1. Iron Accumulation Promotes Aβ Pathology
2.4.2. Iron Accumulation Promotes Tau Pathology
2.5. Hypothesis 3: Iron Accumulation Protects from or Hinders the Accumulation of Misfolded Protein Pathology
2.6. Hypothesis 4: Iron Dyshomeostasis and Protein Accumulation Are Parallel and Converging Pathways
2.7. Conclusion: Iron Dysregulation in AD Pathogenesis
3. Progressive Supranuclear Palsy
3.1. Iron Dysregulation in PSP
3.2. Cellular Iron Dysregulation in PSP
3.3. Hypothesis 2: Iron Accumulation Promotes PSP-Related Tau Pathology
3.4. Conclusion: Iron Dysregulation in PSP Pathogenesis
4. Parkinson’s Disease
4.1. Iron Dysregulation in PD
4.2. Cellular Iron Dysregulation in PD
4.3. Hypothesis 1: Iron Accumulation Is a Consequence of Pathological Alterations in α-Synuclein
4.4. Hypothesis 2: Iron Accumulation Promotes α-Synuclein Pathology
4.5. Hypothesis 3: Iron Accumulation Protects from or Hinders the Accumulation of Misfolded Protein Pathology
4.6. Hypothesis 4: Iron Dyshomeostasis and Protein Accumulation Are Parallel and Converging Pathways
4.7. Conclusion: Iron Dysregulation in PD Pathogenesis
5. Multiple System Atrophy
5.1. Iron Dysregulation in MSA
5.2. Cellular Iron Dysregulation in MSA
5.3. MSA-Specific Evidence of Iron Involvement in Disease Pathogenesis
5.4. Conclusion: Iron Dysregulation in MSA Pathogenesis
6. Synthesis and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Hypothesis | Study | Sample Model | Relevant Findings |
---|---|---|---|
Hypothesis 1 (Aβ) | Dekens et al. [48] | Primary astrocytic culture | Addition of human recombinant Aβ in culture medium resulted in increased ferritin expression. |
Baringer et al. [39] | iPSC-derived endothelial cells and astrocytes | Aβ exposure led to increased iron uptake by astrocytes and iron transport across the blood–brain barrier model of endothelial cells. | |
McIntosh et al. [50] | Primary microglial culture and APPswe/PS1dE9 mice | IFNγ and Aβ exposure led to increased glial iron retention. | |
Li et al. [51] | WT C57/B16 mice | Intrahippocampal injection of Aβ oligomers induced increased APP expression and iron accumulation. | |
Tsatsanis et al. [46] | Primary neuronal culture | Inhibition of α-secretase activity led to increased cellular iron retention. | |
Hypothesis 1 (tau) | Lei et al. [42] | Primary neuronal culture and Tau KO C57BL/6/SV129 mice | Tau KO led to cellular iron retention and iron accumulation in the cortex, hippocampus, and the substantia nigra. |
Hypothesis 2 (Aβ) | Banerjee et al. [58] | SHSY5Y cells and monomeric Aβ42 | Ferric ammonium citrate (FAC) treatment induced increased β-secretase activity and Aβ42 secretion, and oligomerization of monomeric Aβ42. |
Chen et al. [59] | Primary neuronal culture | FAC treatment induced abnormal cellular localization of soluble APP α. | |
Becerill-Ortega et al. [60] | Primary neuronal and astrocytic culture and APP/PS1 mice | Iron exposure led to neuronal-specific increase in KPI-APP (pro-amyloidogenic form) expression and secretion of Aβ42. | |
Chen et al. [61] | APP/PS1 mice | Dietary iron treatment led to increased Aβ in the hippocampus. | |
Tahmasebinia and Emadi [62] | Aβ40 and Aβ42 peptides | Ferric chloride treatment promoted the aggregation of Aβ40 and Aβ42 peptides. | |
Hypothesis 2 (tau) | Wan et al. [66] | Primary neuronal culture and C57BL/6 mice | Iron treatment led to increased phosphorylation at Ser202/Thr205, Thr181, and Ser396 sites of tau. |
Yamamoto et al. [68] | PHF-tau from post-mortem AD tissue | Ferric iron bound to hyperphosphorylated tau and induced aggregation in a dose-dependent manner. | |
Ahmadi et al. [69] | Tau-410 | Ferrous and ferric iron bound to tau and induced structural changes. | |
Guo et al. [67] | APP/PS1 mice | Iron-rich diet resulted in increased phosphorylation of tau at Thr205, Thr231, and Ser396 sites. | |
Hypothesis 3 | - | - | - |
Hypothesis 4 | - | - | - |
Hypothesis | Study | Sample Model | Relevant Findings |
---|---|---|---|
Hypothesis 1 | Please refer to Table 1, rows under “Hypothesis 1 (tau)”. | ||
Hypothesis 2 | Mukherjee and Panda [96] | 4R2N recombinant tau | Ferric iron induced tau oligomerization and fibrillization in a dose-dependent manner. |
For more information, please refer to Table 1, rows under “Hypothesis 2 (tau)”. | |||
Hypothesis 3 | - | - | - |
Hypothesis 4 | - | - | - |
Hypothesis | Study | Sample Model | Relevant Findings |
---|---|---|---|
Hypothesis 1 | Guo et al. [127] | Macaca fascicularis | Administration of pre-formed α-syn fibrils resulted in robust iron deposition in the SN and GP, localized to microglia, and altered iron homeostatic protein expression in dopaminergic neurons. |
Deas et al. [134] | iPSC-derived neuron with SNCA triplication mutation | Exposure to exogenous α-syn oligomeric species resulted in iron-induced oxidative stress. | |
Mi et al. [136] | MES23.5 dopaminergic cells | Addition of recombinant α-syn to culture media induced dysregulation of iron homeostatic genes. | |
Ortega et al. [137] | Primary neuronal culture | Overexpression of human α-syn in an iron-rich environment resulted in increased intracellular iron retention. | |
Hypothesis 2 | Zhao et al. [148] | Human recombinant α-syn | Incubation with ferric iron promoted α-syn fibrillization at low concentrations. |
Abeyawardhane et al. [149] | Human recombinant α-syn | Under aerobic conditions, ferrous iron incubation induced a soluble α-syn oligomer structure, and ferric iron induced a fibril structure with β-sheets, both of elevated toxic species. | |
Uversky et al. [150] | Human recombinant α-syn | Incubation with ferric iron induced accelerated and increased aggregation of α-syn. | |
Kostka et al. [151] | Human recombinant α-syn | Incubation with ferric iron enhanced α-syn aggregation, producing larger and toxic oligomers. | |
Li et al. [152] | Human recombinant α-syn and HEK293 cells | Incubation with ferric iron enhanced the seeded aggregation of α-syn in a dose-dependent manner, demonstrating enhanced intracellular aggregation and transcellular propagation of α-syn; iron-seeded fibrils were more cytotoxic. | |
Ostrerova-Golts et al. [153] | Human BE-M17 neuroblastoma cells transfected with WT, A53T, A30P α-syn | Treatment with ferrous iron induced a dose-dependent formation of high-molecular-weight α-syn aggregates in A53T α-syn-expressing cells. | |
Agostini et al. [154] | α-syn-overexpressing dopaminergic neuron Drosophila model | Administration of ferric ammonium citrate accelerated α-syn pathology formation in dopaminergic neurons and reduced fly life span. | |
Xiao et al. [139] | Dopaminergic cell line SN4741 | Ferrous iron promoted α-syn aggregation and secretion via inhibition of autophagosome–lysosome fusion. | |
Wang et al. [155] | Sprague Dawley rats and SH-SY5Y cells | Iron upregulated α-syn phosphorylation at Ser129 and high-molecular-weight-α-syn levels in the SN and dopaminergic cells. | |
Li et al. [140] | SK-N-SH cells | Ferrous and ferric iron induced cell loss and α-syn aggregation, both directly and via oxidative stress. | |
Hypothesis 3 | Dauer Née Joppe et al. [156] | C57BI/6J mice and primary neuronal culture | Neonatal iron-enriched mice showed significantly less α-syn pathology in connectome-specific regions. |
Hypothesis 4 | Ortega et al. [137] | Primary neuronal culture | Overexpression of α-syn in an iron-rich environment resulted in increased intracellular iron retention, which could not be induced via either α-syn overexpression or iron enrichment alone. |
Osterova-Golts et al. [153] | Human BE-M17 neuroblastoma cells transfected with WT, A53T, A30P α-syn | Cells overexpressing all types of α-syn were more vulnerable to iron-induced toxicity. | |
Mahoney-Sanchez et al. [159] | LUHMES cells (human dopaminergic neuronal model) | α-syn KO prevented ferroptosis. |
Hypothesis 1 | Hypothesis 2 | Hypothesis 3 | Hypothesis 4 | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
MRI | PM | AM | IV | MRI | PM | AM | IV | MRI | PM | AM | IV | MRI | PM | AM | IV | |
AD (Aβ) | ||||||||||||||||
AD (tau) | ||||||||||||||||
PSP | ||||||||||||||||
PD | ||||||||||||||||
MSA |
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Lee, S.; Kovacs, G.G. The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases. Int. J. Mol. Sci. 2024, 25, 4269. https://doi.org/10.3390/ijms25084269
Lee S, Kovacs GG. The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases. International Journal of Molecular Sciences. 2024; 25(8):4269. https://doi.org/10.3390/ijms25084269
Chicago/Turabian StyleLee, Seojin, and Gabor G. Kovacs. 2024. "The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases" International Journal of Molecular Sciences 25, no. 8: 4269. https://doi.org/10.3390/ijms25084269