1. Please check and comment entries here.
Table of Contents

    Topic review

    Iron Homeostasis

    Subjects: Clinical Neurology
    View times: 27
    Submitted by:

    Definition

    Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, these cells secrete diffusible mediators that reshape neuronal iron homeostasis and regulate iron entry into the brain.

    1. Introduction

    Brain iron overload in neurodegeneration-prone areas and in neuroinflammation has been broadly recognized as a pathological hallmark of neurodegenerative diseases, such Alzheimer’s disease (AD) and Parkinson’s disease (PD). Neuroinflammation refers to the inflammatory responses mediated by the innate immune system that take place in the central nervous system (CNS). Although it shares many features with peripheral inflammation, the coexistence of CNS specialized cell types, such as microglia, astrocytes, neurons, endothelial cells, and pericytes, confers unique characteristics to brain inflammation. Furthermore, the loss of integrity of the blood–brain barrier (BBB) found in neuroinflammatory conditions allows the infiltration of peripheral inflammatory cells, such as macrophages [1].

    The initiation of the progressive inflammatory process in AD and PD can be traced to the neurodegeneration of noradrenergic (NA) neurons in the locus coeruleus (LC), which is the earliest and more severely affected area in PD (Braak stage 2), followed by dopaminergic neurons of substantia nigra (SN; Braak stage 3) and ultimately, by the neurodegeneration of hippocampal and cortical neurons (Braak stage 5) [2]. Interestingly, in the most recent Braak staging of AD, tau pathology is first observed in the LC, later spreading to the entorhinal cortex and finally to other neocortical regions [3][4][5], suggesting shared molecular mechanisms with PD [6].

    The selective vulnerability of LC-NA neurons correlates with their higher production of reactive oxygen species (ROS) under physiological conditions, which is significantly potentiated by peripheral inflammation, resulting in mitochondrial damage. An elevated expression of neuronal NADPH oxidase (NOX), which catalyzes the production of the superoxide radical (O2), plays an important role in the selective susceptibility of LC-NA neurons [7]. Interestingly, LC neurodegeneration can be triggered by an intraperitoneal lipopolysaccharide (LPS) injection [8], suggesting that a gut–brain axis may play a significative role in PD pathogenesis, probably associated with a “body-first” PD subtype [9].

    In the brain, norepinephrine (NE) significantly contributes to the suppression of neuroinflammatory responses, by attenuating microglial surveillance and activation, reducing the secretion of proinflammatory factors, and decreasing phagocytic NOX2-mediated ·O2 production [10][11][12][13][14]. Accordingly, the use of N-(2-chloroethyl)-N-ethyl-2-bromo-benzylamine (DSP-4), which is a selective NE toxin, potentiates neuroinflammation induced by amyloid β (Aβ)1–42 aggregates [15] or bacterial endotoxin lipopolysaccharide (LPS) [16][17] and promotes AD and PD pathogenesis in several animal models [16][18][19][20][21][22][23][24][25][26].

    Microglia/macrophage activation can be followed during the progression of neurodegeneration by non-invasive techniques, such as positron emission tomography (PET), using radiotracers specifically designed for targeting the mitochondrial translocator protein 18-kDa (TSPO), which is a protein highly expressed in activated microglia/macrophages. Microglial/macrophage activation has been observed using PET in monkeys injected with the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is a toxin that selectively kills dopaminergic neurons [27][28], and in rats expressing human A53T mutated α-synuclein in SN [29][30] or injected with the highly oxidable dopamine analog 6-hydroxydopamine (6-OHDA) [31][32]. Altered glial immune responses have also been observed in animal models of familial PD [33][34] and in transgenic mice expressing AD-associated mutant proteins [35][36]. An increase in TSPO binding has been consistently observed in studies with AD [37] and PD [38] patients. However, there are several concerns about potential artifacts in microglial TSPO PET imaging, including binding to multiple cell types, such as astrocytes and endothelial cells [39][40]; differential tracer affinity in TSPO Ala147Thr polymorphism carriers [41]; and other confounding factors [42][43]. Therefore, the conclusions of these studies should be interpreted with caution. Interestingly, a recent study on AD transgenic rats shows TSPO upregulation in astrocytes before microglia [44], urging the development of more specific tracers for studying the respective contributions of astrogliosis and microgliosis to the neurodegenerative process. Overall, the reported evidence points to a central role of neuroinflammation in the initiation and progression of neurodegenerative processes.

    The activation of microglial cells triggers the release of diffusible mediators, including cytokines, ROS, and reactive nitrogen species (RNS). Remarkably, ROS/RNS generation is supported by two enzymatic systems: The NOX2 enzyme complex that synthesizes ·O2, which, through its dismutation, generates hydrogen peroxide (H2O2), and the inducible form of nitric oxide synthase (iNOS), which generates ·NO. These enzymatic systems play a crucial role in AD- and PD-associated neurodegeneration, as revealed by the neuroprotection achieved by the pharmacological or genetic inhibition of NOX2 or iNOS reported in animal models of AD [45][46] and PD [47][48][49][50].

    Clinical evidence from patients displaying chronic use of non-steroidal anti-inflammatory drugs (NSAID) shows a reduced risk for AD [51][52] and PD [53]. Based on these epidemiological observations and the beneficial effects of NSAID in AD animal models, several clinical trials have been conducted to assess their efficacy in AD and dementia. Unfortunately, these studies have shown no significant effects on the cognitive performance in AD patients, prompting improvement of the therapeutic window and the use of more selective inhibitors in future clinical trials (reviewed in [54]).

    Recently, neuroinflammation has been associated with the alteration of iron homeostasis, and at the same time, iron dyshomeostasis has been shown to play a pivotal role in the neuroinflammatory phenotype. As a result, neuroinflammation and iron are entangled in a circuit that amplifies ROS production, leading to neuronal death. An analysis of postmortem tissue from PD patients shows significant elevations in the concentration of iron in the SN, where degenerating neuromelanin-bearing dopaminergic neurons reside [55][56]. Similarly, iron is concentrated in and around AD senile plaques [57][58], in Huntington’s disease basal ganglia [59], and in the spinal cord of sporadic amyotrophic lateral sclerosis patients [60]. Due to its paramagnetic property, iron’s content can be estimated in specific brain areas using magnetic resonance imaging (MRI), by measuring the R2* relaxation rate, phase changes in susceptibility-weighted imaging (SWI), or susceptivity values upon quantitative susceptibility mapping (QSM) [61][62][63]. Neuromelanin-sensitive MRI has also been proposed as a diagnostic tool for PD [64]. Significant increases in iron levels are measured in vivo by iron-sensitive MRI, even in the early stages of AD and PD patients, showing a good correlation with the severity of their symptoms [63][65][66]. Patients with familial PD-associated mutations also display increased brain iron deposition by MRI, even in asymptomatic stages [67], suggesting that iron accumulation plays a role in the progression of the idiopathic and genetic forms of PD.

    Iron overload is also associated with several animal models of AD and PD. Transgenic mice for Amyloid precursor protein/presenilin-1 (APP/PS1) [68][69][70][71] and 5xFAD [72] exhibit increased brain iron levels. Moreover, an injection of MPTP, rotenone, or 6-OHDA phenocopies many aspects of PD in rodents, including iron accumulation in the SN [73][74][75]. Supporting a causal role of iron accumulation in neurodegeneration, neonatal iron supplementation in mice triggers the progressive neurodegeneration of SN dopaminergic neurons, reduces striatal dopamine levels, and increases the responsiveness to MPTP insult [76]. Moreover, chronic oral administration of iron induces iron accumulation in specific brain regions, including the SN and caudate/putamen. Iron accumulation is associated with oxidative stress-related dopaminergic neuronal apoptosis in the SN and with motor and cognitive deficits [77]. Consequently, iron chelation prevents neuronal death in several animal models of AD and PD [78][79][80][81][82] and iron chelation has recently been introduced as a new therapeutic concept for the treatment of PD [83][84]. Nevertheless, the results on the use of iron chelation treatment demonstrate that it slows that disease progression [85]. Due to the multifactorial nature of the neurodegenerative process in PD, a single target treatment, such as the use of chelators, may not fully stop the neurodegenerative process. Accordingly, treatment with multifunctional compounds with an iron chelating capacity and aimed at reducing two or more of the pathological events associated with the progress of the disease (a “multi-target” approach) may be better suited for the treatment of PD [85][86].

    Aging is the main risk factor for the development of sporadic forms of AD and PD, and both iron accumulation and neuroinflammation exhibit an age-synchronous increment in the brain. Iron levels and microglial and astrocytic numbers are positively correlated in aged mice basal ganglia [87] and iron-retentive microglia concurring with elevated iron levels and oxidative stress in aged non-human primates [88]. Interestingly, a genetic predisposition to neuroinflammation aggravates the striatal iron-related poor cognitive switching ability in aged humans [89], highlighting the intimate relationship between iron and neuroinflammation during aging (reviewed in [90]).

    2. Iron Homeostasis in the CNS

    Iron is an essential protein cofactor that performs a myriad of unique functions in the CNS, including ribosome assembly, DNA repair, mitochondrial energy production, metabolite catabolism, myelination, and neurotransmitter anabolism and catabolism [91]. In excess, however, iron is linked to cellular death, causing sustained cellular oxidative stress by the iron-mediated catalytic conversion of H2O2 and ·O2 into toxic hydroxyl radicals as a result of Fenton and Haber–Weiss chemistry, respectively [92]. Accordingly, iron homeostasis must be tightly controlled.

    Transferrin (Tf), which is a glycoprotein that possesses two high-affinity iron (III)-binding sites, is the primary iron transporter into the CNS and thus plays an essential role in cellular iron uptake. Following transferrin binding to its surface receptor, TfR1, the Tf-TfR1 complex is endocytosed through clathrin-dependent pathways into the early endosome, in which its low pH induces iron dissociation from Tf. The ferrireductase Steap2 reduces Fe3+ to Fe2+, which is transported into the cytoplasm by the divalent metal transporter-1 (DMT1). The apoTf/TfR1 complex returns to the plasma membrane, where the neutral pH induces its dissociation [93][94].

    In the cytoplasm, iron is incorporated into the cytosolic labile iron pool (cLIP), which is distributed to three destinations: (i) To mitochondria, for the synthesis of iron-sulfur (Fe-S) clusters and heme prosthetic groups; (ii) to the cytoplasmic iron storage protein ferritin (Fn); or (iii) back to the extracellular fluid through the iron exporter, Fpn1. Ferritin is a multimeric protein assembled by 24 subunits of H and L monomers in a variable ratio, depending on the cellular type. The H subunit contains ferroxidase activity, while the L subunit is responsible for iron turnover at the ferroxidase site and iron nucleation within the Fn core [95].

    Iron delivery to the brain is tightly regulated at the level of the BBB [94], composed of tight junction-adhered endothelial cells that safeguard the free access of molecules to the brain. Iron transport across the BBB is mediated by three mechanisms. Overall, the mechanism of iron transport across the BBB involves two transmembrane steps: Iron uptake at the luminal membrane of the brain capillary endothelial cells, followed by iron efflux into the brain interstitium at the abluminal membrane. The predominant mechanism involves the transcellular transport of iron through Tf endocytosis, DMT1-mediated transport from the endosome lumen into the cytoplasm, and Fpn1-mediated extrusion at the abluminal membrane [96][97][98]. A second mechanism involves Tf/TfR1 complex transcytosis across the endothelial cell and the release of Tf into the parenchyma at the abluminal membrane [99]. A third mechanism is dependent on Fn, which is present in blood serum and cerebrospinal fluid (CSF) [100][101][102]. Serum Fn is mainly composed of L subunits with one or two H subunits [95]. Both in vitro and in vivo studies have shown the transport of Fn across the BBB, utilizing different receptors [103][104][105]. The Scara5 receptor recognizes L-Fn [106], while H-Fn binds to TfR1 [107].

    Iron released by brain vascular endothelial cells is quickly captured by nearby astrocytes, which play a critical role in regulating brain iron absorption at the abluminal side. Astrocytes do not express TfR1; however, DMT1 expression is highly polarized in astrocytes, in which DMT1 is mainly found in the end-foot processes associated with the BBB [108]. Therefore, iron released by the endothelial cells is probably taken up by nearby astrocytes through DMT1 and distributed to the brain parenchyma through Fpn1 [109]. The concentration of iron in the CSF ranges between 0.2 and 1.1 µM, whereas the concentration of Tf is about 0.24 µM [110][111]. Therefore, CSF iron levels often exceed the binding capacity of Tf [112] and iron is incorporated by neurons and glia from two sources: Transferrin-bound iron (TBI), through the Tf-TfR1 system, and non-transferrin bound iron (NTBI), through DMT1 or other iron transporters.

    This entry is adapted from 10.3390/antiox10010061

    References

    1. Abe, N.; Nishihara, T.; Yorozuya, T.; Tanaka, J. Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems. Cells 2020, 9, 2132, doi:10.3390/cells9092132.
    2. Braak, H.; Ghebremedhin, E.; Rub, U.; Bratzke, H.; Del Tredici, K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004, 318, 121–134, doi:10.1007/s00441-004-0956-9.
    3. Sun, W.; Tang, Y.; Qiao, Y.; Ge, X.; Mather, M.; Ringman, J.M.; Shi, Y. A probabilistic atlas of locus coeruleus pathways to transentorhinal cortex for connectome imaging in Alzheimer’s disease. Neuroimage 2020, 223, 117301, doi:10.1016/j.neuroimage.2020.117301.
    4. Braak, H.; Thal, D.R.; Ghebremedhin, E.; Del Tredici, K. Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years. Neuropathol. Exp. Neurol. 2011, 70, 960–969, doi:10.1097/NEN.0b013e318232a379.
    5. Theofilas, P.; Ehrenberg, A.J.; Dunlop, S.; Alho, A.T.D.L.; Nguy, A.; Leite, R.E.P.; Rodriguez, R.D.; Mejia, M.B.; Suemoto, C.K.; Ferretti-Rebustini, R.E.L.; et al. Locus coeruleus volume and cell population changes during Alzheimer’s disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 2017, 13, 236–246, doi:10.1016/j.jalz.2016.06.2362.
    6. Kang, S.S.; Liu, X.; Ahn, E.H.; Xiang, J.; Manfredsson, F.P.; Yang, X.; Luo, H.R.; Liles, L.C.; Weinshenker, D.; Ye, K. Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus. Clin. Investig. 2020, 130, 422–437, doi:10.1172/JCI130513.
    7. Wang, Q.; Oyarzabal, E.A.; Song, S.; Wilson, B.; Santos, J.H.; Hong, J.S. Locus coeruleus neurons are most sensitive to chronic neuroinflammation-induced neurodegeneration. Brain Behav. Immun. 2020, 87, 359–368, doi:10.1016/j.bbi.2020.01.003.
    8. Song, S.; Jiang, L.; Oyarzabal, E.A.; Wilson, B.; Li, Z.; Shih, Y.I.; Wang, Q.; Hong, J.S. Loss of Brain Norepinephrine Elicits Neuroinflammation-Mediated Oxidative Injury and Selective Caudo-Rostral Neurodegeneration. Neurobiol. 2019, 56, 2653–2669, doi:10.1007/s12035-018-1235-1.
    9. Horsager, J.; Andersen, K.B.; Knudsen, K.; Skjaerbaek, C.; Fedorova, T.D.; Okkels, N.; Schaeffer, E.; Bonkat, S.K.; Geday, J.; Otto, M.; et al. Brain-first versus body-first Parkinson’s disease: A multimodal imaging case-control study. Brain 2020, 143, 3077–3088, doi:10.1093/brain/awaa238.
    10. Jiang, L.; Chen, S.-H.; Chu, C.-H.; Wang, S.-J.; Oyarzabal, E.; Wilson, B.; Sanders, V.; Xie, K.; Wang, Q.; Hong, J.-S. A novel role of microglial NADPH oxidase in mediating extra-synaptic function of norepinephrine in regulating brain immune homeostasis. Glia 2015, 63, 1057–1072, doi:10.1002/glia.22801.
    11. Yssel, J.D.; O’Neill, E.; Nolan, Y.M.; Connor, T.J.; Harkin, A. Treatment with the noradrenaline re-uptake inhibitor atomoxetine alone and in combination with the alpha2-adrenoceptor antagonist idazoxan attenuates loss of dopamine and associated motor deficits in the LPS inflammatory rat model of Parkinson’s disease. Brain Behav. Immun. 2018, 69, 456–469, doi:10.1016/j.bbi.2018.01.004.
    12. Bharani, K.L.; Derex, R.; Granholm, A.C.; Ledreux, A. A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats. PLoS ONE 2017, 12, e0189821, doi:10.1371/journal.pone.0189821.
    13. Liu, Y.U.; Ying, Y.; Li, Y.; Eyo, U.B.; Chen, T.; Zheng, J.; Umpierre, A.D.; Zhu, J.; Bosco, D.B.; Dong, H.; et al. Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling. Neurosci. 2019, 22, 1771–1781, doi:10.1038/s41593-019-0511-3.
    14. Stowell, R.D.; Sipe, G.O.; Dawes, R.P.; Batchelor, H.N.; Lordy, K.A.; Whitelaw, B.S.; Stoessel, M.B.; Bidlack, J.M.; Brown, E.; Sur, M.; et al. Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex. Neurosci. 2019, 22, 1782–1792, doi:10.1038/s41593-019-0514-0.
    15. Heneka, M.T.; Galea, E.; Gavriluyk, V.; Dumitrescu-Ozimek, L.; Daeschner, J.; O’Banion, M.K.; Weinberg, G.; Klockgether, T.; Feinstein, D.L. Noradrenergic depletion potentiates beta-amyloid-induced cortical inflammation: Implications for Alzheimer's disease. Neurosci. 2002, 22, 2434–2442, doi:20026222.
    16. Song, S.; Wang, Q.; Jiang, L.; Oyarzabal, E.; Riddick, N.V.; Wilson, B.; Moy, S.S.; Shih, Y.I.; Hong, J.S. Noradrenergic dysfunction accelerates LPS-elicited inflammation-related ascending sequential neurodegeneration and deficits in non-motor/motor functions. Brain Behav. Immun. 2019, 81, 374–387, doi:10.1016/j.bbi.2019.06.034.
    17. Yao, N.; Wu, Y.; Zhou, Y.; Ju, L.; Liu, Y.; Ju, R.; Duan, D.; Xu, Q. Lesion of the locus coeruleus aggravates dopaminergic neuron degeneration by modulating microglial function in mouse models of Parkinsons disease. Brain Res. 2015, 1625, 255–274, doi:10.1016/j.brainres.2015.08.032.
    18. Song, S.; Liu, J.; Zhang, F.; Hong, J.S. Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in alpha-synuclein mutant mice. Rep. 2020, 10, 1–13, doi:10.1038/s41598-020-72202-4.
    19. Heneka, M.T.; Ramanathan, M.; Jacobs, A.H.; Dumitrescu-Ozimek, L.; Bilkei-Gorzo, A.; Debeir, T.; Sastre, M.; Galldiks, N.; Zimmer, A.; Hoehn, M.; et al. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. Neurosci. 2006, 26, 1343–1354, doi:10.1523/JNEUROSCI.4236-05.2006.
    20. Kalinin, S.; Gavrilyuk, V.; Polak, P.E.; Vasser, R.; Zhao, J.; Heneka, M.T.; Feinstein, D.L. Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer’s disease. Aging 2007, 28, 1206–1214, doi:10.1016/j.neurobiolaging.2006.06.003.
    21. Heneka, M.T.; Nadrigny, F.; Regen, T.; Martinez-Hernandez, A.; Dumitrescu-Ozimek, L.; Terwel, D.; Jardanhazi-Kurutz, D.; Walter, J.; Kirchhoff, F.; Hanisch, U.K.; et al. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Natl. Acad. Sci. USA 2010, 107, 6058–6063, doi:10.1073/pnas.0909586107.
    22. Duffy, K.B.; Ray, B.; Lahiri, D.K.; Tilmont, E.M.; Tinkler, G.P.; Herbert, R.L.; Greig, N.H.; Ingram, D.K.; Ottinger, M.A.; Mattison, J.A. Effects of Reducing Norepinephrine Levels via DSP4 Treatment on Amyloid-beta Pathology in Female Rhesus Macaques (Macaca Mulatta). Alzheimers Dis. 2019, 68, 115–126, doi:10.3233/JAD-180487.
    23. Ghosh, A.; Torraville, S.E.; Mukherjee, B.; Walling, S.G.; Martin, G.M.; Harley, C.W.; Yuan, Q. An experimental model of Braak’s pretangle proposal for the origin of Alzheimer’s disease: The role of locus coeruleus in early symptom development. Alzheimers Res. Ther. 2019, 11, 1–17, doi:10.1186/s13195-019-0511-2.
    24. Bjerken, S.A.; Persson, R.S.; Barkander, A.; Karalija, N.; Pelegrina-Hidalgo, N.; Gerhardt, G.A.; Virel, A.; Stromberg, I. Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance. Int. 2019, 131, 104551, doi:10.1016/j.neuint.2019.104551.
    25. Evans, A.K.; Ardestani, P.M.; Yi, B.; Park, H.H.; Lam, R.K.; Shamloo, M. Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer’s Disease. Dis. 2020, 146, 105089, doi:10.1016/j.nbd.2020.105089.
    26. Hou, L.; Sun, F.; Sun, W.; Zhang, L.; Wang, Q. Lesion of the Locus Coeruleus Damages Learning and Memory Performance in Paraquat and Maneb-induced Mouse Parkinson’s Disease Model. Neuroscience 2019, 419, 129–140, doi:10.1016/j.neuroscience.2019.09.006.
    27. Zammit, M.; Tao, Y.; Olsen, M.E.; Metzger, J.; Vermilyea, S.C.; Bjornson, K.; Slesarev, M.; Block, W.F.; Fuchs, K.; Phillips, S.; et al. [(18)F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates. EJNMMI Res. 2020, 10, 93, doi:10.1186/s13550-020-00683-5.
    28. Joers, V.; Masilamoni, G.; Kempf, D.; Weiss, A.R.; Rotterman, T.M.; Murray, B.; Yalcin-Cakmakli, G.; Voll, R.J.; Goodman, M.M.; Howell, L.; et al. Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series. Dis. 2020, 144, 105027, doi:10.1016/j.nbd.2020.105027.
    29. Rodriguez-Chinchilla, T.; Quiroga-Varela, A.; Molinet-Dronda, F.; Belloso-Iguerategui, A.; Merino-Galan, L.; Jimenez-Urbieta, H.; Gago, B.; Rodriguez-Oroz, M.C. [(18)F]-DPA-714 PET as a specific in vivo marker of early microglial activation in a rat model of progressive dopaminergic degeneration. J. Nucl. Med. Mol. Imaging 2020, 47, 2602–2612, doi:10.1007/s00259-020-04772-4.
    30. Crabbe, M.; Van Der Perren, A.; Bollaerts, I.; Kounelis, S.; Baekelandt, V.; Bormans, G.; Casteels, C.; Moons, L.; Van Laere, K. Increased P2X7 Receptor Binding Is Associated With Neuroinflammation in Acute but Not Chronic Rodent Models for Parkinson’s Disease. Neurosci. 2019, 13, 799, doi:10.3389/fnins.2019.00799.
    31. Wu, C.Y.; Chen, Y.Y.; Lin, J.J.; Li, J.P.; Chen, J.K.; Hsieh, T.C.; Kao, C.H. Development of a novel radioligand for imaging 18-kD translocator protein (TSPO) in a rat model of Parkinson’s disease. BMC Med. Imaging 2019, 19, 78, doi:10.1186/s12880-019-0375-8.
    32. Vetel, S.; Serriere, S.; Vercouillie, J.; Vergote, J.; Chicheri, G.; Deloye, J.B.; Dolle, F.; Bodard, S.; Tronel, C.; Nadal-Desbarats, L.; et al. Extensive exploration of a novel rat model of Parkinson’s disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches. Synapse 2019, 73, e22077, doi:10.1002/syn.22077.
    33. Sun, L.; Shen, R.; Agnihotri, S.K.; Chen, Y.; Huang, Z.; Bueler, H. Lack of PINK1 alters glia innate immune responses and enhances inflammation-induced, nitric oxide-mediated neuron death. Rep. 2018, 8, 383, doi:10.1038/s41598-017-18786-w.
    34. Chien, C.H.; Lee, M.J.; Liou, H.C.; Liou, H.H.; Fu, W.M. Microglia-Derived Cytokines/Chemokines Are Involved in the Enhancement of LPS-Induced Loss of Nigrostriatal Dopaminergic Neurons in DJ-1 Knockout Mice. PLoS ONE 2016, 11, e0151569, doi:10.1371/journal.pone.0151569.
    35. Hu, W.; Pan, D.; Wang, Y.; Bao, W.; Zuo, C.; Guan, Y.; Hua, F.; Yang, M.; Zhao, J. PET Imaging for Dynamically Monitoring Neuroinflammation in APP/PS1 Mouse Model Using [(18)F]DPA714. Neurosci. 2020, 14, 810, doi:10.3389/fnins.2020.00810.
    36. Sacher, C.; Blume, T.; Beyer, L.; Peters, F.; Eckenweber, F.; Sgobio, C.; Deussing, M.; Albert, N.L.; Unterrainer, M.; Lindner, S.; et al. Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-beta Mouse Model. Nucl. Med. 2019, 60, 1787–1793, doi:10.2967/jnumed.119.227322.
    37. Tournier, B.B.; Tsartsalis, S.; Ceyzeriat, K.; Garibotto, V.; Millet, P. In Vivo TSPO Signal and Neuroinflammation in Alzheimer’s Disease. Cells 2020, 9, 1941, doi:10.3390/cells9091941.
    38. Belloli, S.; Morari, M.; Murtaj, V.; Valtorta, S.; Moresco, R.M.; Gilardi, M.C. Translation Imaging in Parkinson’s Disease: Focus on Neuroinflammation. Aging Neurosci. 2020, 12, 152, doi:10.3389/fnagi.2020.00152.
    39. Pannell, M.; Economopoulos, V.; Wilson, T.C.; Kersemans, V.; Isenegger, P.G.; Larkin, J.R.; Smart, S.; Gilchrist, S.; Gouverneur, V.; Sibson, N.R. Imaging of translocator protein upregulation is selective for pro-inflammatory polarized astrocytes and microglia. Glia 2020, 68, 280–297, doi:10.1002/glia.23716.
    40. Tournier, B.B.; Tsartsalis, S.; Ceyzeriat, K.; Medina, Z.; Fraser, B.H.; Gregoire, M.C.; Kovari, E.; Millet, P. Fluorescence-activated cell sorting to reveal the cell origin of radioligand binding. Cereb. Blood Flow Metab. 2020, 40, 1242–1255, doi:10.1177/0271678X19860408.
    41. Owen, D.R.; Yeo, A.J.; Gunn, R.N.; Song, K.; Wadsworth, G.; Lewis, A.; Rhodes, C.; Pulford, D.J.; Bennacef, I.; Parker, C.A.; et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. Cereb. Blood Flow Metab. 2012, 32, 1–5, doi:10.1038/jcbfm.2011.147.
    42. Laurell, G.L.; Plaven-Sigray, P.; Jucaite, A.; Varrone, A.; Cosgrove, K.P.; Svarer, C.; Knudsen, G.M.; Ogden, R.T.; Zanderigo, F.; Cervenka, S.; et al. Non-displaceable binding is a potential confounding factor in (11)CPBR28 TSPO PET studies. Nucl. Med. 2020, 10, doi:10.2967/jnumed.120.243717.
    43. Kim, S.W.; Wiers, C.E.; Tyler, R.; Shokri-Kojori, E.; Jang, Y.J.; Zehra, A.; Freeman, C.; Ramirez, V.; Lindgren, E.; Miller, G.; et al. Influence of alcoholism and cholesterol on TSPO binding in brain: PET [(11)C]PBR28 studies in humans and rodents. Neuropsychopharmacology 2018, 43, 1832–1839, doi:10.1038/s41386-018-0085-x.
    44. Tournier, B.B.; Tsartsalis, S.; Ceyzeriat, K.; Fraser, B.H.; Gregoire, M.C.; Kovari, E.; Millet, P. Astrocytic TSPO Upregulation Appears Before Microglial TSPO in Alzheimer’s Disease. Alzheimers Dis. 2020, 77, 1043–1056, doi:10.3233/JAD-200136.
    45. Gong, P.; Chen, Y.Q.; Lin, A.H.; Zhang, H.B.; Zhang, Y.; Ye, R.D.; Yu, Y. p47(phox) deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD. Alzheimers Res. Ther. 2020, 12, 146, doi:10.1186/s13195-020-00714-2.
    46. Geng, L.; Fan, L.M.; Liu, F.; Smith, C.; Li, J. Nox2 dependent redox-regulation of microglial response to amyloid-beta stimulation and microgliosis in aging. Rep. 2020, 10, 1582, doi:10.1038/s41598-020-58422-8.
    47. Liberatore, G.T.; Jackson-Lewis, V.; Vukosavic, S.; Mandir, A.S.; Vila, M.; McAuliffe, W.G.; Dawson, V.L.; Dawson, T.M.; Przedborski, S. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Med. 1999, 5, 1403–1409, doi:10.1038/70978.
    48. Dehmer, T.; Lindenau, J.; Haid, S.; Dichgans, J.; Schulz, J.B. Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. Neurochem 2000, 74, 2213–2216, doi:10.1046/j.1471-4159.2000.0742213.x.
    49. Smith, T.S.; Swerdlow, R.H.; Parker, W.D., Jr.; Bennett, J.P., Jr. Reduction of MPP(+)-induced hydroxyl radical formation and nigrostriatal MPTP toxicity by inhibiting nitric oxide synthase. Neuroreport 1994, 5, 2598–2600, doi:10.1097/00001756-199412000-00048.
    50. Qin, L.; Liu, Y.; Wang, T.; Wei, S.J.; Block, M.L.; Wilson, B.; Liu, B.; Hong, J.S. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. Biol. Chem. 2004, 279, 1415–1421, doi:10.1074/jbc.M307657200.
    51. McGeer, P.L.; Schulzer, M.; McGeer, E.G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: A review of 17 epidemiologic studies. Neurology 1996, 47, 425–432, doi:10.1212/wnl.47.2.425.
    52. Wang, J.; Tan, L.; Wang, H.F.; Tan, C.C.; Meng, X.F.; Wang, C.; Tang, S.W.; Yu, J.T. Anti-inflammatory drugs and risk of Alzheimer’s disease: An updated systematic review and meta-analysis. Alzheimers Dis. 2015, 44, 385–396, doi:10.3233/JAD-141506.
    53. Gagne, J.J.; Power, M.C. Anti-inflammatory drugs and risk of Parkinson disease: A meta-analysis. Neurology 2010, 74, 995–1002, doi:10.1212/WNL.0b013e3181d5a4a3.
    54. Moore, A.H.; Bigbee, M.J.; Boynton, G.E.; Wakeham, C.M.; Rosenheim, H.M.; Staral, C.J.; Morrissey, J.L.; Hund, A.K. Non-Steroidal Anti-Inflammatory Drugs in Alzheimer’s Disease and Parkinson's Disease: Reconsidering the Role of Neuroinflammation. Pharmaceuticals 2010, 3, 1812–1841, doi:10.3390/ph3061812.
    55. Sofic, E.; Riederer, P.; Heinsen, H.; Beckmann, H.; Reynolds, G.P.; Hebenstreit, G.; Youdim, M.B. Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. Neural Transm. 1988, 74, 199–205, doi:10.1007/BF01244786.
    56. Griffiths, P.D.; Crossman, A.R. Distribution of iron in the basal ganglia and neocortex in postmortem tissue in Parkinson's disease and Alzheimer’s disease. Dementia 1993, 4, 61–65, doi:10.1159/000107298.
    57. Connor, J.R.; Menzies, S.L.; St Martin, S.M.; Mufson, E.J. A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains. Neurosci. Res. 1992, 31, 75–83, doi:10.1002/jnr.490310111.
    58. Grundke-Iqbal, I.; Fleming, J.; Tung, Y.C.; Lassmann, H.; Iqbal, K.; Joshi, J.G. Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia. Acta Neuropathol. 1990, 81, 105–110, doi:10.1007/BF00334497.
    59. Dexter, D.T.; Carayon, A.; Javoy-Agid, F.; Agid, Y.; Wells, F.R.; Daniel, S.E.; Lees, A.J.; Jenner, P.; Marsden, C.D. Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 1991, 114, 1953–1975, doi:10.1093/brain/114.4.1953.
    60. Kasarskis, E.J.; Tandon, L.; Lovell, M.A.; Ehmann, W.D. Aluminum, calcium, and iron in the spinal cord of patients with sporadic amyotrophic lateral sclerosis using laser microprobe mass spectroscopy: A preliminary study. Neurol. Sci. 1995, 130, 203–208, doi:10.1016/0022-510x(95)00037-3.
    61. Arribarat, G.; De Barros, A.; Peran, P. Modern Brainstem MRI Techniques for the Diagnosis of Parkinson’s Disease and Parkinsonisms. Neurol. 2020, 11, 791, doi:10.3389/fneur.2020.00791.
    62. Barbosa, J.H.; Santos, A.C.; Tumas, V.; Liu, M.; Zheng, W.; Haacke, E.M.; Salmon, C.E. Quantifying brain iron deposition in patients with Parkinson’s disease using quantitative susceptibility mapping, R2 and R2. Reson. Imaging 2015, 33, 559–565, doi:10.1016/j.mri.2015.02.021.
    63. Pyatigorskaya, N.; Sanz-Morere, C.B.; Gaurav, R.; Biondetti, E.; Valabregue, R.; Santin, M.; Yahia-Cherif, L.; Lehericy, S. Iron Imaging as a Diagnostic Tool for Parkinson’s Disease: A Systematic Review and Meta-Analysis. Neurol. 2020, 11, 366, doi:10.3389/fneur.2020.00366.
    64. Wang, X.; Zhang, Y.; Zhu, C.; Li, G.; Kang, J.; Chen, F.; Yang, L. The diagnostic value of SNpc using NM-MRI in Parkinson's disease: Meta-analysis. Sci. 2019, 40, 2479–2489, doi:10.1007/s10072-019-04014-y.
    65. Wang, J.Y.; Zhuang, Q.Q.; Zhu, L.B.; Zhu, H.; Li, T.; Li, R.; Chen, S.F.; Huang, C.P.; Zhang, X.; Zhu, J.H. Meta-analysis of brain iron levels of Parkinson’s disease patients determined by postmortem and MRI measurements. Rep. 2016, 6, 36669, doi:10.1038/srep36669.
    66. Du, L.; Zhao, Z.; Cui, A.; Zhu, Y.; Zhang, L.; Liu, J.; Shi, S.; Fu, C.; Han, X.; Gao, W.; et al. Increased Iron Deposition on Brain Quantitative Susceptibility Mapping Correlates with Decreased Cognitive Function in Alzheimer’s Disease. ACS Chem. Neurosci. 2018, 9, 1849–1857, doi:10.1021/acschemneuro.8b00194.
    67. Pyatigorskaya, N.; Sharman, M.; Corvol, J.C.; Valabregue, R.; Yahia-Cherif, L.; Poupon, F.; Cormier-Dequaire, F.; Siebner, H.; Klebe, S.; Vidailhet, M.; et al. High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry. Disord. 2015, 30, 1077–1084, doi:10.1002/mds.26218.
    68. Svobodova, H.; Kosnac, D.; Balazsiova, Z.; Tanila, H.; Miettinen, P.O.; Sierra, A.; Vitovic, P.; Wagner, A.; Polak, S.; Kopani, M. Elevated age-related cortical iron, ferritin and amyloid plaques in APP(swe)/PS1(deltaE9) transgenic mouse model of Alzheimer’s disease. Res. 2019, 68, S445–S451, doi:10.33549/physiolres.934383.
    69. McIntosh, A.; Mela, V.; Harty, C.; Minogue, A.M.; Costello, D.A.; Kerskens, C.; Lynch, M.A. Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice. Brain Pathol. 2019, 29, 606–621, doi:10.1111/bpa.12704.
    70. Telling, N.D.; Everett, J.; Collingwood, J.F.; Dobson, J.; van der Laan, G.; Gallagher, J.J.; Wang, J.; Hitchcock, A.P. Iron Biochemistry is Correlated with Amyloid Plaque Morphology in an Established Mouse Model of Alzheimer’s Disease. Cell Chem. Biol. 2017, 24, 1205–1215 e1203, doi:10.1016/j.chembiol.2017.07.014.
    71. Dong, X.-h.; Gao, W.-j.; Shao, T.-m.; Xie, H.-l.; Bai, J.-t.; Zhao, J.y.; Chai, X.-q. Age-related changes of brain iron load changes in the frontal cortex in APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer’s disease. Trace Elem. Med. Biol 2015, 30, 118–123, doi:10.1016/j.jtemb.2014.11.009.
    72. Gurel, B.; Cansev, M.; Sevinc, C.; Kelestemur, S.; Ocalan, B.; Cakir, A.; Aydin, S.; Kahveci, N.; Ozansoy, M.; Taskapilioglu, O.; et al. Early Stage Alterations in CA1 Extracellular Region Proteins Indicate Dysregulation of IL6 and Iron Homeostasis in the 5XFAD Alzheimer’s Disease Mouse Model. Alzheimers Dis. 2018, 61, 1399–1410, doi:10.3233/JAD-170329.
    73. Mochizuki, H.; Imai, H.; Endo, K.; Yokomizo, K.; Murata, Y.; Hattori, N.; Mizuno, Y. Iron accumulation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys. Lett. 1994, 168, 251–253, doi:10.1016/0304-3940(94)90462-6.
    74. Xiong, P.; Chen, X.; Guo, C.; Zhang, N.; Ma, B. Baicalin and deferoxamine alleviate iron accumulation in different brain regions of Parkinson’s disease rats. Neural Regen. Res. 2012, 7, 2092–2098, doi:10.3969/j.issn.1673-5374.2012.27.002.
    75. Oestreicher, E.; Sengstock, G.J.; Riederer, P.; Olanow, C.W.; Dunn, A.J.; Arendash, G.W. Degeneration of nigrostriatal dopaminergic neurons increases iron within the substantia nigra: A histochemical and neurochemical study. Brain Res. 1994, 660, 8–18, doi:10.1016/0006-8993(94)90833-8.
    76. Kaur, D.; Peng, J.; Chinta, S.J.; Rajagopalan, S.; Di Monte, D.A.; Cherny, R.A.; Andersen, J.K. Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Aging 2007, 28, 907–913, doi:10.1016/j.neurobiolaging.2006.04.003.
    77. Huang, C.; Ma, W.; Luo, Q.; Shi, L.; Xia, Y.; Lao, C.; Liu, W.; Zou, Y.; Cheng, A.; Shi, R.; et al. Iron overload resulting from the chronic oral administration of ferric citrate induces parkinsonism phenotypes in middle-aged mice. Aging 2019, 11, 9846–9861, doi:10.18632/aging.102433.
    78. Ben-Shachar, D.; Eshel, G.; Finberg, J.P.; Youdim, M.B. The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. Neurochem. 1991, 56, 1441–1444, doi:10.1111/j.1471-4159.1991.tb11444.x.
    79. Kaur, D.; Yantiri, F.; Rajagopalan, S.; Kumar, J.; Mo, J.Q.; Boonplueang, R.; Viswanath, V.; Jacobs, R.; Yang, L.; Beal, M.F.; et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: A novel therapy for Parkinson’s disease. Neuron 2003, 37, 899–909, doi:10.1016/s0896-6273(03)00126-0.
    80. Youdim, M.B.; Stephenson, G.; Ben Shachar, D. Ironing iron out in Parkinson’s disease and other neurodegenerative diseases with iron chelators: A lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28. N. Y. Acad. Sci. 2004, 1012, 306–325, doi:10.1196/annals.1306.025.
    81. Mena, N.P.; Garcia-Beltran, O.; Lourido, F.; Urrutia, P.J.; Mena, R.; Castro-Castillo, V.; Cassels, B.K.; Nunez, M.T. The novel mitochondrial iron chelator 5-((methylamino)methyl)-8-hydroxyquinoline protects against mitochondrial-induced oxidative damage and neuronal death. Biophys. Res. Commun. 2015, 463, 787–792, doi:10.1016/j.bbrc.2015.06.014.
    82. Rao, S.S.; Portbury, S.D.; Lago, L.; Bush, A.I.; Adlard, P.A. The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy. Alzheimers. Dis. 2020, 77, 753–771, doi:10.3233/JAD-200551.
    83. Devos, D.; Moreau, C.; Devedjian, J.C.; Kluza, J.; Petrault, M.; Laloux, C.; Jonneaux, A.; Ryckewaert, G.; Garcon, G.; Rouaix, N.; et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Redox. Signal 2014, 21, 195–210, doi:10.1089/ars.2013.5593.
    84. Martin-Bastida, A.; Ward, R.J.; Newbould, R.; Piccini, P.; Sharp, D.; Kabba, C.; Patel, M.C.; Spino, M.; Connelly, J.; Tricta, F.; et al. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Rep. 2017, 7, 1398, doi:10.1038/s41598-017-01402-2.
    85. Nunez, M.T.; Chana-Cuevas, P. New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases. Pharmaceuticals 2018, 11, doi:10.3390/ph11040109.
    86. Nunez, M.T.; Chana-Cuevas, P. New perspectives in iron chelation therapy for the treatment of Parkinson’s disease. Neural Regen. Res. 2019, 14, 1905–1906, doi:10.4103/1673-5374.259614.
    87. Ashraf, A.; Michaelides, C.; Walker, T.A.; Ekonomou, A.; Suessmilch, M.; Sriskanthanathan, A.; Abraha, S.; Parkes, A.; Parkes, H.G.; Geraki, K.; et al. Regional Distributions of Iron, Copper and Zinc and Their Relationships With Glia in a Normal Aging Mouse Model. Aging Neurosci. 2019, 11, 351, doi:10.3389/fnagi.2019.00351.
    88. Rodriguez-Callejas, J.D.; Cuervo-Zanatta, D.; Rosas-Arellano, A.; Fonta, C.; Fuchs, E.; Perez-Cruz, C. Loss of ferritin-positive microglia relates to increased iron, RNA oxidation, and dystrophic microglia in the brains of aged male marmosets. J. Primatol. 2019, 81, e22956, doi:10.1002/ajp.22956.
    89. Daugherty, A.M.; Hoagey, D.A.; Kennedy, K.M.; Rodrigue, K.M. Genetic predisposition for inflammation exacerbates effects of striatal iron content on cognitive switching ability in healthy aging. Neuroimage 2019, 185, 471–478, doi:10.1016/j.neuroimage.2018.10.064.
    90. Ashraf, A.; Clark, M.; So, P.W. The Aging of Iron Man. Aging Neurosci. 2018, 10, 65, doi:10.3389/fnagi.2018.00065.
    91. Andreini, C.; Putignano, V.; Rosato, A.; Banci, L. The human iron-proteome. Metallomics 2018, 10, 1223–1231, doi:10.1039/c8mt00146d.
    92. Halliwell, B. Biochemistry of oxidative stress. Soc. Trans. 2007, 35, 1147–1150, doi:10.1042/BST0351147.
    93. Johnsen, K.B.; Burkhart, A.; Thomsen, L.B.; Andresen, T.L.; Moos, T. Targeting the transferrin receptor for brain drug delivery. Neurobiol. 2019, 181, 101665, doi:10.1016/j.pneurobio.2019.101665.
    94. Duck, K.A.; Connor, J.R. Iron uptake and transport across physiological barriers. Biometals 2016, 29, 573–591, doi:10.1007/s10534-016-9952-2.
    95. Arosio, P.; Ingrassia, R.; Cavadini, P. Ferritins: A family of molecules for iron storage, antioxidation and more. Biophys. Acta 2009, 1790, 589–599, doi:10.1016/j.bbagen.2008.09.004.
    96. McCarthy, R.C.; Kosman, D.J. Iron transport across the blood-brain barrier: Development, neurovascular regulation and cerebral amyloid angiopathy. Cell Mol. Life Sci. 2015, 72, 709–727, doi:10.1007/s00018-014-1771-4.
    97. Qian, Z.M.; Ke, Y. Brain iron transport. Rev. Camb. Philos. Soc. 2019, 94, 1672–1684, doi:10.1111/brv.12521.
    98. Wade, Q.W.; Chiou, B.; Connor, J.R. Iron uptake at the blood-brain barrier is influenced by sex and genotype. Pharmacol. 2019, 84, 123–145, doi:10.1016/bs.apha.2019.02.005.
    99. Skarlatos, S.; Yoshikawa, T.; Pardridge, W.M. Transport of [125I]transferrin through the rat blood-brain barrier. Brain Res. 1995, 683, 164–171, doi:10.1016/0006-8993(95)00363-u.
    100. Cohen, L.A.; Gutierrez, L.; Weiss, A.; Leichtmann-Bardoogo, Y.; Zhang, D.L.; Crooks, D.R.; Sougrat, R.; Morgenstern, A.; Galy, B.; Hentze, M.W.; et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 2010, 116, 1574–1584, doi:10.1182/blood-2009-11-253815.
    101. Sun, Q.; Yang, F.; Wang, H.; Cui, F.; Li, Y.; Li, S.; Ren, Y.; Lan, W.; Li, M.; Zhu, W.; et al. Elevated serum ferritin level as a predictor of reduced survival in patients with sporadic amyotrophic lateral sclerosis in China: A retrospective study. Lateral Scler. Front. Degener. 2019, 20, 186–191, doi:10.1080/21678421.2018.1555599.
    102. Li, R.; Luo, C.; Mines, M.; Zhang, J.; Fan, G.H. Chemokine CXCL12 induces binding of ferritin heavy chain to the chemokine receptor CXCR4, alters CXCR4 signaling, and induces phosphorylation and nuclear translocation of ferritin heavy chain. Biol. Chem. 2006, 281, 37616–37627, doi:10.1074/jbc.M607266200.
    103. Fisher, J.; Devraj, K.; Ingram, J.; Slagle-Webb, B.; Madhankumar, A.B.; Liu, X.; Klinger, M.; Simpson, I.A.; Connor, J.R. Ferritin: A novel mechanism for delivery of iron to the brain and other organs. J. Physiol. Cell Physiol. 2007, 293, C641–C649, doi:10.1152/ajpcell.00599.2006.
    104. Chiou, B.; Neal, E.H.; Bowman, A.B.; Lippmann, E.S.; Simpson, I.A.; Connor, J.R. Endothelial cells are critical regulators of iron transport in a model of the human blood-brain barrier. Cereb. Blood Flow Metab. 2019, 39, 2117–2131, doi:10.1177/0271678X18783372.
    105. Chiou, B.; Connor, J.R. Emerging and Dynamic Biomedical Uses of Ferritin. Pharmaceuticals 2018, 11, 124, doi:10.3390/ph11040124.
    106. Li, J.Y.; Paragas, N.; Ned, R.M.; Qiu, A.; Viltard, M.; Leete, T.; Drexler, I.R.; Chen, X.; Sanna-Cherchi, S.; Mohammed, F.; et al. Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Cell 2009, 16, 35–46, doi:10.1016/j.devcel.2008.12.002.
    107. Li, L.; Fang, C.J.; Ryan, J.C.; Niemi, E.C.; Lebron, J.A.; Bjorkman, P.J.; Arase, H.; Torti, F.M.; Torti, S.V.; Nakamura, M.C.; et al. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Natl. Acad. Sci. USA 2010, 107, 3505–3510, doi:10.1073/pnas.0913192107.
    108. Wang, X.S.; Ong, W.Y.; Connor, J.R. A light and electron microscopic study of the iron transporter protein DMT-1 in the monkey cerebral neocortex and hippocampus. Neurocytol. 2001, 30, 353–360, doi:10.1023/a:1014464514793.
    109. Dringen, R.; Bishop, G.M.; Koeppe, M.; Dang, T.N.; Robinson, S.R. The pivotal role of astrocytes in the metabolism of iron in the brain. Res. 2007, 32, 1884–1890, doi:10.1007/s11064-007-9375-0.
    110. Moos, T.; Morgan, E.H. Evidence for low molecular weight, non-transferrin-bound iron in rat brain and cerebrospinal fluid. Neurosci. Res. 1998, 54, 486–494, doi:10.1002/(SICI)1097-4547(19981115)54:4<486::AID-JNR6>3.0.CO;2-I.
    111. Gilbert, B.C. Free Radicals and Iron: Chemistry, Biology and Medicine; Symons, M.C.R., Gutteridge, J.M.C., Eds.; Oxford University Press, Oxford, UK, 1998; ISBN 0-19-855892-9.
    112. Moos, T.; Rosengren Nielsen, T.; Skjorringe, T.; Morgan, E.H. Iron trafficking inside the brain. Neurochem. 2007, 103, 1730–1740, doi:10.1111/j.1471-4159.2007.04976.x.
    More