Iron Overload in Brain: Transport Mismatches, Microbleeding Events, and How Nanochelating Therapies May Counteract Their Effects
Abstract
:1. Introduction
2. Iron: A (New) Responsive Biomarker
2.1. Iron Detection
2.2. Iron-Related Damaging Mechanisms in CNS
2.2.1. Direct Mechanisms
2.2.2. Indirect Mechanisms
- Humanin belongs to a family of mitochondrial-derived peptides (MIDPs), and it is a peptide encoded by the mitochondrial genome. It is associated with life extension and possesses antioxidant and protective functions within the mitochondrion [49]. In AD, levels of Humanin decrease [50]. Notably, Humanin is produced in mitochondria and has the ability to enhance the survival of these organelles under conditions of excessive iron accumulation. Specific Single Nucleotide Polymorphisms (SNPs) of Humanin have been identified, with NP rs2854128 showing an inverse correlation with Humanin levels in the blood of elderly individuals [51]. This SNP may have implications for AD pathogenesis and could serve as a potential genetic marker.
- Appoptosin (Solute carrier family 25 member 38—SLC25A38), also known as Mitochondrial glycine transporter (GlyC) or SLC25A38, plays a crucial role in heme synthesis by facilitating the transport of glycine required for the initial step of heme biosynthesis into the mitochondrion. Appoptosin is involved in neuron death associated with neurodegeneration [52]. In AD, Appoptosin is upregulated [52]. The heme biosynthetic pathway involves the insertion of iron as the final step. Therefore, along with glycine, mitochondria must import iron using the transporter Mitoferrin (Mf) and store it in the Frataxin protein to prevent toxicity until it is utilized. An SNP (rs1768208, C/T) associated with progressive supranuclear palsy is located near the MOB gene on chromosome 3 and is correlated with increased expression of Appoptosin, whose gene is approximately 70 kb apart from MOB [53]. Moreover, in schizophrenia, a Genome-wide association analysis (GWAS) identified an association between SNP rs56055643 on chromosome 3, the expression of SLC25A38 (Appoptosin gene), and hippocampal dentate gyrus volume [54]. These associations indicate the potential involvement of Appoptosin in AD and other neurological disorders.
- Mitoferrin and Frataxin modulate the amount of iron imported into the mitochondrion and stored in a non-toxic form. They are regulated by hypoxia via HIF-1a [55]. In human degenerative pathologies, there is only one data point in Huntington Disease, in which both Mf2 increases and frataxin (the mitochondrial analogue of ferritin) decreases [56], while in human AD there is no experimental evidence such as protein expression.
- Phosphatidylinositol-binding clathrin assembly protein (PICALM) acts as a modulator of the internalization of TfR (transferrin receptor), therefore modulating the entry of iron into cells. The PICALM gene is considered a risk factor for LOAD (late-onset AD). The PICALM SNP rs10792832 has been studied in association with APOE4 and BIN1 SNPs in AD risk [57]. Furthermore, the SNP rs3851179 is included in the list of SNPs that correlate most with the risk of AD [58].
- APOE-ε4 is considered a strong risk factor for sporadic AD. As said before, it is an inhibitor of ferritinophagy [42]. The fluid concentrations of ApoE and its different isoforms in AD patients and among APOE genotypes remain controversial. In fact, one study reported that ApoE content in CSF is not an indicator of AD progression and that there is no association between plasma levels of total ApoE or its isoforms and AD biomarkers [59]. Instead, another study observed in the CSF of AD an increase in total ApoE content and an alteration of the ApoE protein, suggesting that function may be compromised [60]. Moreover, there is strong evidence for the association between AD and APOE-4 polymorphisms and for the association with at least two SNPs located less than 16 kb from APOE [61].
2.3. Where Does the Iron Excess in the Brain Come From?
- Iron concentration in blood (mg/L)—red compartment;
- Iron concentration in CSF (mg/L)—blue compartment;
- Iron concentration in ISF (mg/L)—yellow compartment;
- Blood → ISF: Kinetic constant rate for iron entering from blood to brain (consequently ISF), across BBB;
- Blood → CSF: Kinetic constant rate for iron entering from blood to CSF across the blood–CSF barrier (BCSFB);
- CSF → ISF: Kinetic constant rate for iron passing from CSF to ISF;
- ISF → Blood: Kinetic constant rate for iron returning from the brain to the blood.
- CSF → Blood: Kinetic constant rate for iron returning from CSF and brain to blood;
- ISF → CSF: Kinetic constant rate for iron passing from ISF to CSF;
2.3.1. Blood → ISF
2.3.2. Blood → CSF and CSF → ISF
2.3.3. ISF → Blood
2.3.4. ISF → CSF and CSF → Blood
2.4. Towards Novel Intrathecal Therapy: The Nano-Chelating Approach
3. Conclusions and Future Perspectives
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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A. Direct Mechanisms | B. Indirect Mechanisms |
---|---|
A1. oxidative stress by Fenton and Haber–Weiss reaction | B1. iron-induced oxidation affects the lipid metabolism regulated by the apolipoprotein |
A2. direct binding to amyloidogenic proteins | B2. altered iron homeostasis leads to mitochondrial dysfunction |
A3. alteration of the spontaneous neuronal activity | B3. iron-calcium interplay modulates neuronal functionality |
A4. enhancement of microbial proliferation | B4. iron-fueled infections enhance amyloid plaques formation |
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Ficiarà, E.; Stura, I.; Vernone, A.; Silvagno, F.; Cavalli, R.; Guiot, C. Iron Overload in Brain: Transport Mismatches, Microbleeding Events, and How Nanochelating Therapies May Counteract Their Effects. Int. J. Mol. Sci. 2024, 25, 2337. https://doi.org/10.3390/ijms25042337
Ficiarà E, Stura I, Vernone A, Silvagno F, Cavalli R, Guiot C. Iron Overload in Brain: Transport Mismatches, Microbleeding Events, and How Nanochelating Therapies May Counteract Their Effects. International Journal of Molecular Sciences. 2024; 25(4):2337. https://doi.org/10.3390/ijms25042337
Chicago/Turabian StyleFiciarà, Eleonora, Ilaria Stura, Annamaria Vernone, Francesca Silvagno, Roberta Cavalli, and Caterina Guiot. 2024. "Iron Overload in Brain: Transport Mismatches, Microbleeding Events, and How Nanochelating Therapies May Counteract Their Effects" International Journal of Molecular Sciences 25, no. 4: 2337. https://doi.org/10.3390/ijms25042337