Next Article in Journal
Cereus jamacaru D.C. Hydroalcoholic Extract Promotes Anti-Cytotoxic and Antitumor Activity
Next Article in Special Issue
Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects
Previous Article in Journal / Special Issue
Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Brain Iron Homeostasis: A Focus on Microglial Iron

Israel C. Nnah
Marianne Wessling-Resnick
Department of Genetics and Complex Diseases, Harvard TH Chan School of Public Health, Boston, MA 02115, USA
Author to whom correspondence should be addressed.
Pharmaceuticals 2018, 11(4), 129;
Submission received: 17 October 2018 / Revised: 16 November 2018 / Accepted: 19 November 2018 / Published: 23 November 2018
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)


Iron is an essential trace element required for important brain functions including oxidative metabolism, synaptic plasticity, myelination, and the synthesis of neurotransmitters. Disruptions in brain iron homeostasis underlie many neurodegenerative diseases. Increasing evidence suggests that accumulation of brain iron and chronic neuroinflammation, characterized by microglia activation and secretion of proinflammatory cytokines, are hallmarks of neurodegenerative disorders including Alzheimer’ s disease. While substantial efforts have led to an increased understanding of iron metabolism and the role of microglial cells in neuroinflammation, important questions still remain unanswered. Whether or not increased brain iron augments the inflammatory responses of microglial cells, including the molecular cues that guide such responses, is still unclear. How these brain macrophages accumulate, store, and utilize intracellular iron to carry out their various functions under normal and disease conditions is incompletely understood. Here, we describe the known and emerging mechanisms involved in microglial cell iron transport and metabolism as well as inflammatory responses in the brain, with a focus on AD.

1. Introduction

The brain is among the most metabolically active organs in the body and accounts for at least 20% of the body’s energy consumption. Accordingly, an adequate supply of iron is necessary to sustain its high-energy needs [1,2,3,4]. Our understanding of the role of iron in normal brain function has improved tremendously over the last decade, with much attention directed towards deciphering the cellular and molecular cues that guide brain iron transport and metabolism. These efforts have described the essential roles of iron as a co-factor for several physiological processes including oxidative metabolism, myelination, and the biosynthesis of neurotransmitters [5,6,7]. However, excess iron is known to contribute to homeostatic dysregulation due to oxidative stress and has been linked to a number of neurological disorders. Being redox active, iron exists in both ferrous (Fe2+) and ferric (Fe3+) forms and constantly cycles between the two states. Under aerobic conditions, this redox cycling has the potential to generate highly reactive free radicals through Fenton chemistry, resulting in oxidative stress and damage to macromolecules. Thus, the metal is directly implicated in the disease known as neurodegeneration with brain iron accumulation (NBIA), and, in addition to other trace elements implicated in neurodegeneration, including copper [8], manganese [9], and zinc [10], increasing evidence support iron’s role in several other sporadic or genetic neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) [11,12,13,14].
Microglia make up 5 to 12% of the population of cells found in mouse brain and about 0.5 to 16% of those in the human brain [15,16]. These resident macrophages are largely involved in immune responses and, depending on the stimuli, they can adopt a range of pro- or anti-inflammatory states to help maintain the integrity of the neural environment [17,18,19]. In addition to their roles in the neuroinflammatory response, microglia participate in neurogenesis [19,20], shaping and maintaining synaptic density and connectivity in the adult and developing central nervous system (CNS) [16,21,22,23,24], oligodendrocyte differentiation [25], synaptic pruning [26], and myelin repair [16]. Microglia require iron as a co-factor to carry out all of these varied functions [27]. Over the years, multiple studies have reported the roles these immune cells play in brain iron homeostasis [1,27,28]. This review will examine the influence of brain iron on microglial metabolism and corresponding inflammatory responses under normal and neurodegenerative conditions, with a particular focus on AD.

2. Brain Iron

Brain iron levels are tightly regulated to ensure the normal function of the CNS [29,30]. The major route of iron acquisition begins with intestinal absorption, as dietary Fe3+ is reduced to Fe2+ by duodenal cytochrome B (DcytB) at the apical surface of enterocytes [31]. Divalent metal transporter-1 (DMT1) imports Fe2+ into the intestinal cells, while the iron exporter ferroportin (Fpn) mediates its exit across this epithelial barrier. On the serosal side, the multicopper ferroxidases ceruloplasmin and/or hephaestin oxidize Fe2+ to Fe3+, thereby promoting its binding to the iron carrier protein transferrin (Tf) [32]. Dietary absorption of iron is tightly regulated to respond to the body’s iron needs, such that uptake is enhanced by iron deficiency but reduced under iron-loading conditions [29]. Thus, iron supplied to the brain from the diet reflects nutrient demands, while limiting the potential for excessive accumulation.
Once in the circulation, the entry of iron into the brain from the blood is controlled by the blood–brain barrier (BBB) [33]. The BBB is formed by brain microvascular endothelial cells (BMVECs), pericytes, and astrocytes [33,34,35]. Tf-bound iron circulating in the blood outside the CNS cannot cross the BBB directly, and, therefore, iron must enter the brain through BMVECs in a multi-step transcellular pathway. Binding of Tf to Tf receptors (TfR) at the lumen of the brain microvasculature facilitates iron uptake via receptor-mediated endocytosis [30,34,36]. The subsequent fate of the Tf–TfR complex within brain endothelial cells is not entirely clear, and exactly how iron is released to the brain remains controversial. The transcytosis model suggests that the ligand–receptor complex traverses the cell, such that Tf is released to the interstitium. However, how Tf might dissociate from its receptor at the abluminal membrane remains unexplained. An alternative model is that iron is released to the cytoplasm of BMVECs after receptor-mediated endocytosis of Tf. The endocytic uptake pathway for iron is much better understood and involves the release of Fe3+ from Tf in the acidic endosomal environment, its reduction to Fe2+, and DMT1-mediated export from the endosome [29]. However, whether BMVECs express DMT1 or if its function is required for entry of iron into the brain is unclear, since different groups have reported conflicting data [37,38,39,40,41,42]. An alternative membrane transport mechanism could involve transient receptor potential mucolipin-1 (TRPML1) channels which function in the release of iron from endolysosomal compartments [43]. A recent study has shown that loss of TRPML1 in mice promotes dysregulation of brain homeostasis and decreased myelination, suggesting a potential role in brain iron uptake [44]. Regardless of which transporter is responsible for iron’s exit from endocytic compartments, the metal would then be utilized for metabolic purposes by the endothelial cells, stored in endothelial cell ferritin (Ftn), or released to the brain via Fpn [45]. Re-oxidation of Fe2+ to Fe3+ and subsequent incorporation into apo-Tf would provide for its circulation in the brain [46,47,48]. It is possible that hepcidin, which is produced by the brain endothelium, plays a role in regulating this process. An in-depth review of iron uptake into BMVECs and its release has been published elsewhere [33].
It is important to note that the amount of Tf in the brain interstitial fluid is thought to be much lower than the levels in the systemic circulation, while non-Tf-bound iron (NTBI) levels may be quite high [49]. Thus, although Tf is apparently involved in moving iron across the BBB, there is some evidence to suggest that Tf-iron-binding sites may become saturated in the brain, such that NTBI is a major source of iron delivery to neurons and other cells in the brain. Another alternative source of iron is ferritin which plays an important role in brain iron homeostasis. In fact, genetic loss of ferritin function leads to brain iron dyshomeostasis [11,50,51,52]. The brain may acquire ferritin exogenously by transcellular transport across the BBB, or it may be produced by endothelial cells and released upon demand [53]. Other endogenous sources of brain ferritin are possible, including its synthesis by microglia [28]. The ferritin pathway of iron delivery is particularly important for mouse oligodendrocytes and their function in myelination and neuronal repair. These express the ferritin receptor Tim-2, a member of the T cell immunoglobulin and mucin domain family, and specifically take up ferritin [6,54]. In humans, the transferrin receptor may bind to and mediate the internalization of ferritin [55,56].

3. Functions of Iron in the Brain

Iron plays an indispensable role during ATP production by serving as a cofactor for cytochromes and iron–sulfur complexes of the oxidative chain [57]. The major substrate for brain energy production is glucose which becomes fully oxidized; ketone bodies can fulfill energy needs under some conditions. The brain consumes nearly 20% of the body’s energy, although representing only about 2% of its weight. About 75–80% of the energy supports neuronal activity, with the remainder utilized to maintain the “housekeeping” functions of astrocytes, oligodendrocytes, and microglia [4]. Neuronal energy needs represent both axonal and synaptic signaling, but the majority is utilized post-synaptically [58]. The mitochondrial function must provide this supply of ATP with the iron requirements to support oxidative phosphorylation, as shown in Figure 1.
Oligodendrocytes, which are responsible for producing myelin, also require high amounts of ATP [59]. Not only do many of the enzymes involved in ATP production require a supply of iron, but also pathways for cholesterol and fatty acid synthesis necessary for myelination are iron-dependent. Some of the enzymes involved in this pathway include NADH dehydrogenase, HMG-CoA reductase, succinate dehydrogenase, dioxygenase, and glucose-6-phosphate dehydrogenase, all of which are abundant in oligodendrocytes compared to other cell types of the CNS [59]. The need for an adequate supply of iron during myelination is reflected in the results of animal studies demonstrating that dietary iron restriction reduces the amount and composition of myelin during gestation and early post-natal periods [60,61].
Neurotransmitters serve as means of communication between neurons. The process of this communication includes biosynthesis and transport of neurotransmitters, packaging of neurotransmitters into vesicles for storage and controlled release, and binding of neurotransmitters to receptors on post-synaptic neurons with induction of cellular responses. The role of iron in each of these processes has been reviewed extensively, particularly in the case of monoamine neurotransmitters such as dopamine and serotonin that are involved in the regulation of cognitive processes including emotion and arousal behaviors [1,62,63,64,65]. For example, the synthesis of monoamine neurotransmitters depends on tyrosine hydroxylase which is an iron-requiring enzyme [66,67]. The activity of this enzyme is significantly reduced in patients suffering from PD with compromised brain iron homeostasis [67]. Iron deficiency further alters the functioning of the dopaminergic systems, with specific effects on dopamine D1 and D2 receptors [1,68]. Studies carried out by Youdim and colleagues demonstrated that the densities of dopamine D2 receptors are significantly lower in the striatum of rats deficient in iron [69,70,71]. Also, microdialysis studies demonstrated an elevation of extracellular dopamine in the striatum of iron-deficient rats and the return to basal levels when brain iron content and iron status returned to normal [72]. In the case of serotonin, tryptophan hydroxylase carries out the rate-determining step in the synthesis of this neurotransmitter and can be inhibited by iron chelators [66,73]. Another neurotransmitter whose biosynthesis is compromised under iron-deficient conditions is gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the CNS. Iron deficiency is associated with significant reduction in the activity of glutamate dehydrogenase and GABA transaminase, key enzymes responsible for the synthesis and degradation of GABA [74,75].

4. Microglia and Iron

Microglial activation in response to pro- and anti-inflammatory stimuli is often characterized either as classical M1 or as alternative M2, similar to the nomenclature used for systemic macrophages [76,77]. M1 activation is pro-inflammatory and neurotoxic and primarily induced through the activation of toll-like receptor (TLR) and interferon gamma (IFN-γ) signaling pathway [19]. M1 microglia synthesize and secrete pro-inflammatory cytokines and chemokines such as tumor necrosis factor-alpha (TNF-α), some members of the interleukin family of cytokines interleukin-6 (IL-6), interleukin 1-beta (IL-1β), interleukin-12 (IL-12), and C-C Motif Chemokine Ligand 2 (CCL2). In this reactive state, microglia also express inducible nitric oxide synthase (iNOS), which converts arginase into nitric oxide [19]. Accumulation of nitric oxide increases the toxic effects of glutamate and consequently potentiates N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity [19,78,79].
In the M2 state, microglia release anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). M2 microglia also induce arginase 1 to promote the conversion of arginine into polyamines [80]. These cells can secrete insulin-like growth factor I (IGF-I), fibroblast growth factor (FGF), and neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in the effort to resolve inflammation and promote synaptic plasticity [19].
The use of the terms “M1 versus M2” oversimplifies a complex process for microglial activity, since transcriptome studies have revealed that activation is quite variable and context-dependent [18,81]. Indeed, microglia adopt a homeostatic (M0) state under normal conditions in the CNS, and their transcriptome profile reflects their immunosurveillance activities in this state [18,81,82,83]. Conversely, microglia can express both neurotoxic and neuroprotective factors under disease conditions [19,81,84].
One prominent hallmark of neuroinflammation is the activation and increased acquisition of extracellular iron and subsequent downregulation of iron-interacting proteins, causing the intracellular sequestration of iron [13]. Systemically, such innate immune responses are orchestrated to deprive invading pathogens of iron, necessary for their survival [85]. This “iron withdrawal” phenomenon could play a similar role in the brain to reduce the metal’s availability. However, accumulation of intracellular iron is associated with neuronal degeneration that underlies most neurological disorders [86], and microglial secretion of the inflammatory cytokines TNF-α and IL-1β enhances neuronal iron uptake [87]. In turn, these pro-inflammatory mediators have been shown to strongly influence microglia iron transport and metabolism [13,88,89,90].
Microglial cells interact with both Tf bound-iron (TBI) and NTBI [91], and pathways for each transport substrate have been characterized [28]. For NTBI uptake, an endogenous cell surface ferrireductase reduces Fe3+ to Fe2+ for uptake by DMT1 in a pH-dependent manner at the cell surface. TBI is taken up by endocytosis of the Tf–TfR complex; after the release of iron in the acidic milieu of the endosome, it is translocated into the cytosol by DMT1 or other transporters, as described above [92].
Early studies of rat microglia raised the idea that microglial polarization and iron uptake are coordinated [89]. More recently, our group has shown that microglial iron transport pathways are differentially active in response to pro- and anti-inflammatory stimuli at both the transcript and the protein levels. Pro-inflammatory mediators increase the uptake of NTBI and expand the ferritin storage pool. These changes reflect the upregulation of both DMT1 and ferritin [28]. The uptake of NTBI by microglia would limit free extracellular iron and reduce potentially damaging reactive oxygen species (ROS) in the neural environment. In this M1 pro-inflammatory state, microglial cells also have increased glycolysis, with extracellular acidification supporting changes in the microenvironment favoring NTBI uptake by the pH-dependent transporter DMT1. Inflammatory mediators also reduce oxidative respiration, induce heme oxygenase-1, and diminish the levels of intracellular heme. These changes are associated with increased intracellular “labile iron”, suggesting that microglia can sequester both intracellular iron released by heme catabolism and extracellular iron taken up by DMT1. In contrast, anti-inflammatory IL-4 increases the expression of TfR to promote the uptake of TBI [28]. It is possible that this shift in iron transport is associated with the release of ferritin stores by M2 microglia to support the regeneration of neurons and the activity of oligodendrocytes. On the basis of these data, we propose a model by which microglia actively modify transport pathways and metabolism in response to the iron status of their environment (Figure 2).

5. Microglia Activation and Alzheimer’s Disease

Alzheimer’s Disease (AD) is a neurodegenerative disorder and the most common form of dementia involving the progressive loss of substantive cortical and hippocampal neurons over time [93,94]. This disorder is characterized by extracellular deposition of amyloid beta (Aβ) in senile plaques and intraneuronal accumulation of hyperphosphorylated tau proteins. These events lead to neuronal and synaptic loss, chronic inflammation, and oxidative stress [19,89,95,96].
Genetic studies of familial Alzheimer’s disease (FAD) have demonstrated that mutations in the amyloid precursor protein and in components of the gamma-secretase complex generate Aβ1-42 which can misfold and aggregate [19,93,97]. The more common sporadic form (SAD) of the disease is largely associated with aging. Although the pathophysiological mechanisms that underlie the role of aging in the onset of AD is poorly understood, accumulating evidence indicates that the onset of SAD is closely associated with brain iron and oxidative stress, both of which increase with age [95,98,99,100,101,102,103]. In AD, the observation that iron is present in local areas of neuronal cell death further supports the metal theory of dementia which proposes that iron promotes neurodegeneration [104]. Furthermore, as brain microglia are implicated in iron handling, it has been shown that iron accumulates in microglial cells that cluster around amyloid plaques in AD mouse models and post-mortem brain tissues of AD patients [105].
Iron is a key player during the induction of oxidative stress because of its function as a redox-active transition metal [13,96,106]. Indeed, the levels of damaging ROS are significantly higher in the AD brain compared to healthy control brains [96,107]. Importantly, several studies have reported that, by promoting neurotoxic oligomerization of Aβ peptides and tau tangles [94,108], oxidative stress potentiates the activation of microglia [96,109,110]. Whether these events advance or hinder the disease is subject to active debate. For example, while anti-inflammatory activities of microglia would appear to be beneficial, some studies have reported that prolonged stimulation of microglia with Aβ peptides provokes chronic inflammation [111].
Microglial cells express multiple receptors including CD36, TLR2, TLR4, and TLR6 [111,112,113], all of which can bind Aβ and induce pro-inflammatory effects. The sporadic form of AD is associated with genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) [114]. TREM2 is an immune transmembrane glycoprotein receptor expressed in microglia that interacts with phospholipids, apoptotic cells, and lipoproteins [115,116,117,118]. These variants, as well as the loss-of-function mouse models of AD, appear to limit microglial proliferation around Aβ plaques, causing increased plaque buildup and disease progression [119,120,121,122]. Why defective TREM2 function or expression impacts microglia responses to AD lesion is still incompletely understood. The role of TREM2 and other immune receptors identified as risk factors, including CD33, have been reviewed elsewhere [19].
SAD is also associated with the polymorphism of apolipoprotein E (apoE), a lipid-binding protein involved in lipid metabolism [123,124,125]. The apoE4 allele is strongly associated with an increased risk of AD, while apoE2 serves a protective role [123]. Microglia produce apoE, which has been shown to moderate the inflammatory response while enhancing the phagocytosis of Aβ aggregates by microglia [124,125,126,127,128]. However, in carriers of apoE4, increased levels of ferritin have been reported in the cerebral spinal fluid, suggesting that iron metabolism is altered in these individuals to promote increased iron retention [129]. This evidence reinforces the concept that increased brain iron adversely affects patients with AD. In fact, patients with HFE-associated hemochromatosis are subject to earlier onset of AD [130]. Since there is clinical evidence that iron chelation is beneficial to AD patients [131,132], the relationship between microglia, iron, and neurodegeneration appears to be well worth exploring.

6. Concluding Remarks

Understanding the role of iron in chronic inflammatory responses elicited by microglia is essential for finding new therapeutic strategies to treat neurodegenerative diseases. Although a substantial amount of effort has been put into deciphering the molecular network directly involved in brain iron metabolism, we still must pursue an in-depth understanding of how specific brain cells accumulate and use iron to carry out their various functions, both in normal and in disease conditions.

Author Contributions

I.C.N. and M.W.-R. wrote, reviewed, and edited this manuscript.


Supported by the National Institutes of Diabetes and Digestive and Kidney Disease under the award R01 DK064750. ICN is supported by the National Institute of Environmental Health Sciences under the award T32 ES016645.

Conflicts of Interest

The authors declare no conflict of interest.


Alzheimer’s diseaseAD
familial Alzheimer’s diseaseFAD
sporadic Alzheimer’s diseaseSAD
neurodegeneration with brain iron accumulationNBIA
Parkinson’s diseasePD
Huntington’s diseaseHD
amyotrophic lateral sclerosisALS
multiple sclerosisMS
amyloid beta
Tf-bound ironTBI
transferrin receptorTfR
non-transferrin-bound ironNTBI
divalent metal transporter-1DMT1
labile iron poolLIP
central nervous systemCNS
Blood–brain barrierBBB
brain microvascular endothelial cellBMVEC
transient receptor potential mucolipin-1TRPML1
reactive oxygen speciesROS
gamma-aminobutyric acidGABA
inducible nitric oxidaseiNOS
adenosine triphosphateATP
3-hydroxy-3-methyl-glutaryl-coenzyme AHMG-CoA
tricarboxylic acidTCA
interferon gammaIFN-γ
toll-like receptorTLR
tumor necrosis factor-alphaTNF-α
interleukin 1-betaIL-1β
C-C motif chemokine ligand-2CCL2
transforming growth factor-betaTGF-β
insulin-like growth factor-1IGF-1
fibroblast growth factorFGF
nerve growth factorNGF
brain-derived growth factorBDNF
toll-like receptor 2TLR2
toll-like receptor 4TLR4
toll-like receptor 6TLR6
cluster of differentiation 33CD33
cluster of differentiation 36CD36
triggering receptor expressed on myeloid cells 2TREM2
apolipoprotein EapoE
apolipoprotein E4apoE4
apolipoprotein E2apoE2


  1. Beard, J.L.; Connor, J.R. Iron status and neural functioning. Annu. Rev. Nutr. 2003, 23, 41–58. [Google Scholar] [CrossRef] [PubMed]
  2. Hidalgo, C.; Carrasco, M.A.; Muñoz, P.; Núñez, M.T. A Role for Reactive Oxygen/Nitrogen Species and Iron on Neuronal Synaptic Plasticity. Antioxid. Redox Signal. 2007, 9, 245–255. [Google Scholar] [CrossRef] [PubMed]
  3. Falkowska, A.; Gutowska, I.; Goschorska, M.; Nowacki, P.; Chlubek, D.; Baranowska-Bosiacka, I. Energy Metabolism of the Brain, Including the Cooperation between Astrocytes and Neurons, Especially in the Context of Glycogen Metabolism. Int. J. Mol. Sci. 2015, 16, 25959–25981. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Magistretti, P.J.; Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 2015, 86, 883–901. [Google Scholar] [CrossRef] [PubMed]
  5. Madsen, E.; Gitlin, J.D. Copper and Iron Disorders of the Brain. Annu. Rev. Neurosci. 2007, 30, 317–337. [Google Scholar] [CrossRef] [PubMed]
  6. Todorich, B.; Zhang, X.; Slagle-Webb, B.; Seaman, W.E.; Connor, J.R. Tim-2 is the receptor for H-ferritin on oligodendrocytes. J. Neurochem. 2008, 107, 1495–1505. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Salvador, G.A. Iron in neuronal function and dysfunction. Biofactors 2010, 36, 103–110. [Google Scholar] [CrossRef] [PubMed]
  8. Giampietro, R.; Spinelli, F.; Contino, M.; Colabufo, N.A. The Pivotal Role of Copper in Neurodegeneration: A New Strategy for the Therapy of Neurodegenerative Disorders. Mol. Pharm. 2018, 15, 808–820. [Google Scholar] [CrossRef] [PubMed]
  9. Bowman, A.B.; Kwakye, G.F.; Herrero Hernandez, E.; Aschner, M. Role of manganese in neurodegenerative diseases. J. Trace Elem. Med. Biol. 2011, 25, 191–203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Szewczyk, B. Zinc homeostasis and neurodegenerative disorders. Front. Aging Neurosci. 2013, 5, 33. [Google Scholar] [CrossRef] [PubMed]
  11. Muhoberac, B.B.; Vidal, R. Abnormal iron homeostasis and neurodegeneration. Front. Aging Neurosci. 2013, 5, 32. [Google Scholar] [CrossRef] [PubMed]
  12. Ward, R.J.; Zucca, F.A.; Duyn, J.H.; Crichton, R.R.; Zecca, L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014, 13, 1045–1060. [Google Scholar] [CrossRef] [Green Version]
  13. Thomsen, M.S.; Andersen, M.V.; Christoffersen, P.R.; Jensen, M.D.; Lichota, J.; Moos, T. Neurodegeneration with inflammation is accompanied by accumulation of iron and ferritin in microglia and neurons. Neurobiol. Dis. 2015, 81, 108–118. [Google Scholar] [CrossRef] [PubMed]
  14. Li, K.; Reichmann, H. Role of Iron in Neurodegenerative Diseases. J. Neural Transm. 2016, 123, 389–399. [Google Scholar] [CrossRef] [PubMed]
  15. Mittelbronn, M.; Dietz, K.; Schluesener, H.J.; Meyermann, R. Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol. 2001, 101, 249–255. [Google Scholar] [PubMed]
  16. Lloyd, A.F.; Davies, C.L.; Miron, V.E. Microglia: Origins, homeostasis, and roles in myelin repair. Curr. Opin. Neurobiol. 2017, 47, 113–120. [Google Scholar] [CrossRef] [PubMed]
  17. Prinz, M.; Tay, T.L.; Wolf, Y.; Jung, S. Microglia: Unique and common features with other tissue macrophages. Acta Neuropathol. 2014, 128, 319–331. [Google Scholar] [CrossRef] [PubMed]
  18. Ransohoff, R.M. A polarizing question: Do M1 and M2 microglia exist? Nat. Neurosci. 2016, 19, 987–991. [Google Scholar] [CrossRef] [PubMed]
  19. Colonna, M.; Butovsky, O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 2017, 35, 441–468. [Google Scholar] [CrossRef] [PubMed]
  20. Squarzoni, P.; Thion, M.S.; Garel, S. Neuronal and microglial regulators of cortical wiring: Usual and novel guideposts. Front. Neurosci. 2015, 9, 248. [Google Scholar] [CrossRef] [PubMed]
  21. Pollard, J.W. Trophic macrophages in development and disease. Nat. Rev. Immunol. 2009, 9, 259–270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Murray, P.J.; Wynn, T.A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 2011, 11, 723–737. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Tremblay, M.E.; Stevens, B.; Sierra, A.; Wake, H.; Bessis, A.; Nimmerjahn, A. The role of microglia in the healthy brain. J. Neurosci. 2011, 31, 16064–16069. [Google Scholar] [CrossRef] [PubMed]
  24. Wake, H.; Moorhouse, A.J.; Miyamoto, A.; Nabekura, J. Microglia: Actively surveying and shaping neuronal circuit structure and function. Trends Neurosci. 2013, 36, 209–217. [Google Scholar] [CrossRef] [PubMed]
  25. Erblich, B.; Zhu, L.; Etgen, A.M.; Dobrenis, K.; Pollard, J.W. Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS ONE 2011, 6, e26317. [Google Scholar] [CrossRef] [PubMed]
  26. Schafer, D.P.; Lehrman, E.K.; Kautzman, A.G.; Koyama, R.; Mardinly, A.R.; Yamasaki, R.; Ransohoff, R.M.; Greenberg, M.E.; Barres, B.A.; Stevens, B. Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner. Neuron 2012, 74, 691–705. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Rathnasamy, G.; Ling, E.-A.; Kaur, C. Consequences of iron accumulation in microglia and its implications in neuropathological conditions. CNS Neurol. Dis. Drug Targets 2013, 12, 785–798. [Google Scholar] [CrossRef]
  28. McCarthy, R.C.; Sosa, J.C.; Gardeck, A.M.; Baez, A.S.; Lee, C.H.; Wessling-Resnick, M. Inflammation-induced iron transport and metabolism by brain microglia. J. Biol. Chem. 2018, 293, 7853–7863. [Google Scholar] [CrossRef] [PubMed]
  29. Hentze, M.W.; Muckenthaler, M.U.; Andrews, N.C. Review Balancing Acts: Molecular Control of Mammalian Iron Metabolism sequences of systemic iron overload result from chronic iron accumulation in tissues. Cell 2004, 117, 285–297. [Google Scholar] [CrossRef]
  30. Moos, T.; Nielsen, T.R.; Skjørringe, T.; Morgan, E.H. Iron trafficking inside the brain. J. Neurochem. 2007, 103, 1730–1740. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Anderson, G.J.; Frazer, D.M. Current understanding of iron homeostasis. Am. J. Clin. Nutr. 2017, 106, 1559S–1566S. [Google Scholar] [CrossRef] [PubMed]
  32. Wessling-Resnick, M. Iron imports. III. Transfer of iron from the mucosa into circulation. Am. J. Physiol. Gastrointest. Liver Physiol. 2006, 290, G1–G6. [Google Scholar] [CrossRef] [PubMed]
  33. 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. [Google Scholar] [CrossRef] [PubMed]
  34. Abbott, N.J.; Rönnbäck, L.; Hansson, E. Astrocyte–endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 2006, 7, 41–53. [Google Scholar] [CrossRef] [PubMed]
  35. Rouault, T.A.; Cooperman, S. Brain Iron Metabolism. Semin. Pediatr. Neurol. 2006, 13, 142–148. [Google Scholar] [CrossRef] [PubMed]
  36. Ke, Y.; Qian, Z.M. Brain iron metabolism: Neurobiology and neurochemistry. Prog. Neurobiol. 2007, 83, 149–173. [Google Scholar] [CrossRef] [PubMed]
  37. Gunshin, H.; Mackenzie, B.; Berger, U.V.; Gunshin, Y.; Romero, M.F.; Boron, W.F.; Nussberger, S.; Gollan, J.L.; Hediger, M.A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997, 388, 482–488. [Google Scholar] [CrossRef] [PubMed]
  38. Burdo, J.R.; Menzies, S.L.; Simpson, I.A.; Garrick, L.M.; Garrick, M.D.; Dolan, K.G.; Haile, D.J.; Beard, J.L.; Connor, J.R. Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J. Neurosci. Res. 2001, 66, 1198–1207. [Google Scholar] [CrossRef] [PubMed]
  39. Siddappa, A.J.M.; Rao, R.B.; Wobken, J.D.; Leibold, E.A.; Connor, J.R.; Georgieff, M.K. Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J. Neurosci. Res. 2002, 68, 761–775. [Google Scholar] [CrossRef] [PubMed]
  40. Enerson, B.E.; Drewes, L.R. The Rat Blood—Brain Barrier Transcriptome. J. Cereb. Blood Flow Metab. 2006, 26, 959–973. [Google Scholar] [CrossRef] [PubMed]
  41. Moos, T.; Skjoerringe, T.; Gosk, S.; Morgan, E.H. Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1. J. Neurochem. 2006, 98, 1946–1958. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Skjorringe, T.; Burkhart, A.; Johnsen, K.B.; Moos, T. Divalent metal transporter 1 (DMT1) in the brain: Implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology. Front. Mol. Neurosci. 2015, 8, 19. [Google Scholar] [PubMed]
  43. Dong, X.-P.; Cheng, X.; Mills, E.; Delling, M.; Wang, F.; Kurz, T.; Xu, H. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 2008, 455, 992–996. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Grishchuk, Y.; Pena, K.A.; Coblentz, J.; King, V.E.; Humphrey, D.M.; Wang, S.L.; Kiselyov, K.I.; Slaugenhaupt, S.A. Impaired myelination and reduced brain ferric iron in the mouse model of mucolipidosis IV. Dis. Models Mech. 2015, 8, 1591–1601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Simpson, I.A.; Ponnuru, P.; Klinger, M.E.; Myers, R.L.; Devraj, K.; Coe, C.L.; Lubach, G.R.; Carruthers, A.; Connor, J.R. A novel model for brain iron uptake: Introducing the concept of regulation. J. Cereb. Blood Flow Metab. 2015, 35, 48–57. [Google Scholar] [CrossRef] [PubMed]
  46. McCarthy, R.C.; Kosman, D.J. Ferroportin and exocytoplasmic ferroxidase activity are required for brain microvascular endothelial cell iron efflux. J. Biol. Chem. 2013, 288, 17932–17940. [Google Scholar] [CrossRef] [PubMed]
  47. McCarthy, R.C.; Kosman, D.J. Glial cell ceruloplasmin and hepcidin differentially regulate iron efflux from brain microvascular endothelial cells. PLoS ONE 2014, 9, e89003. [Google Scholar] [CrossRef] [PubMed]
  48. Duck, K.A.; Connor, J.R. Iron uptake and transport across physiological barriers. Biometals 2016, 29, 573–591. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Gutteridge, J.M. Ferrous ions detected in cerebrospinal fluid by using bleomycin and DNA damage. Clin. Sci. 1992, 82, 315–320. [Google Scholar] [CrossRef] [PubMed]
  50. Ferreira, C.; Bucchini, D.; Martin, M.E.; Levi, S.; Arosio, P.; Grandchamp, B.; Beaumont, C. Early embryonic lethality of H ferritin gene deletion in mice. J. Biol. Chem. 2000, 275, 3021–3024. [Google Scholar] [CrossRef] [PubMed]
  51. Thompson, K.; Menzies, S.; Muckenthaler, M.; Torti, F.M.; Wood, T.; Torti, S.V.; Hentze, M.W.; Beard, J.; Connor, J. Mouse brains deficient in H-ferritin have normal iron concentration but a protein profile of iron deficiency and increased evidence of oxidative stress. J. Neurosci. Res. 2003, 71, 46–63. [Google Scholar] [CrossRef] [PubMed]
  52. Li, W.; Garringer, H.J.; Goodwin, C.B.; Richine, B.; Acton, A.; VanDuyn, N.; Muhoberac, B.B.; Irimia-Dominguez, J.; Chan, R.J.; Peacock, M.; et al. Systemic and Cerebral Iron Homeostasis in Ferritin Knock-Out Mice. PLoS ONE 2015, 10, e0117435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. 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. J. Cereb. Blood Flow Metab. 2018. [Google Scholar] [CrossRef] [PubMed]
  54. Todorich, B.; Zhang, X.; Connor, J.R. H-ferritin is the major source of iron for oligodendrocytes. Glia 2011, 59, 927–935. [Google Scholar] [CrossRef] [PubMed]
  55. 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. Proc. Natl. Acad. Sci. USA 2010, 107, 3505–3510. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Sakamoto, S.; Kawabata, H.; Masuda, T.; Uchiyama, T.; Mizumoto, C.; Ohmori, K.; Koeffler, H.P.; Kadowaki, N.; Takaori-Kondo, A. H-Ferritin Is Preferentially Incorporated by Human Erythroid Cells through Transferrin Receptor 1 in a Threshold-Dependent Manner. PLoS ONE 2015, 10, e0139915. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Lill, R.; Hoffmann, B.; Molik, S.; Pierik, A.J.; Rietzschel, N.; Stehling, O.; Uzarska, M.A.; Webert, H.; Wilbrecht, C.; Mühlenhoff, U. The role of mitochondria in cellular iron–sulfur protein biogenesis and iron metabolism. Biochim. Biophys. Acta (BBA) Mol. Cell Res. 2012, 1823, 1491–1508. [Google Scholar] [CrossRef] [PubMed]
  58. Alle, H.; Roth, A.; Geiger, J.R.P. Energy-efficient action potentials in hippocampal mossy fibers. Science 2009, 325, 1405–1408. [Google Scholar] [CrossRef] [PubMed]
  59. Todorich, B.; Pasquini, J.M.; Garcia, C.I.; Paez, P.M.; Connor, J.R. Oligodendrocytes and myelination: The role of iron. Glia 2009, 57, 467–478. [Google Scholar] [CrossRef] [PubMed]
  60. Yu, G.S.; Steinkirchner, T.M.; Rao, G.A.; Larkin, E.C. Effect of prenatal iron deficiency on myelination in rat pups. Am. J. Pathol. 1986, 125, 620–624. [Google Scholar] [PubMed]
  61. Ortiz, E.; Pasquini, J.M.; Thompson, K.; Felt, B.; Butkus, G.; Beard, J.; Connor, J.R. Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. J. Neurosci. Res. 2004, 77, 681–689. [Google Scholar] [CrossRef] [PubMed]
  62. Ashkenazi, R.; Ben-Shachar, D.; Youdim, M.B.H. Nutritional iron and dopamine binding sites in the rat brain. Pharmacol. Biochem. Behav. 1982, 17, 43–47. [Google Scholar] [CrossRef]
  63. Adhami, V.M.; Husain, R.; Husain, R.; Seth, P.K. Influence of Iron Deficiency and Lead Treatment on Behavior and Cerebellar and Hippocampal Polyamine Levels in Neonatal Rats. Neurochem. Res. 1996, 21, 915–922. [Google Scholar] [CrossRef] [PubMed]
  64. Kwik-Uribe, C.L.; Gietzen, D.; German, J.B.; Golub, M.S.; Keen, C.L. Chronic Marginal Iron Intakes during Early Development in Mice Result in Persistent Changes in Dopamine Metabolism and Myelin Composition. J. Nutr. 2000, 130, 2821–2830. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Kim, J.; Wessling-Resnick, M. Iron and mechanisms of emotional behavior. J. Nutr. Biochem. 2014, 25, 1101–1107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Kuhn, D.M.; Ruskin, B.; Lovenberg, W. Tryptophan Hydroxylase The role of oxygen, iron, and sulfhydryl groups as determinants of stability and catalytic activity. J. Biol. Chem. 1980, 255, 4137–4143. [Google Scholar] [PubMed]
  67. Glinka, Y.; Gassen, M.; Youdim, M.B.H. Iron and Neurotransmitter Function in the Brain. In Metals and Oxidative Damage in Neurological Disorders; Connor, J.R., Ed.; Springer: Boston, MA, USA, 1997; pp. 1–22. [Google Scholar]
  68. Bianco, L.E.; Wiesinger, J.; Earley, C.J.; Jones, B.C.; Beard, J.L. Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats. J. Neurochem. 2008, 106, 205–215. [Google Scholar] [CrossRef] [PubMed]
  69. Yehuda, S.; Youdim, M.B. Brain iron: A lesson from animal models. Am. J. Clin. Nutr. 1989, 50, 618–629. [Google Scholar] [CrossRef] [PubMed]
  70. Yehuda, S. Neurochemical basis of behavioral effects of brain iron deficiency in animals. In Brain, Behavior and Iron in the Infant Diet; Dobbing, J., Ed.; Springer: London, UK, 1990; pp. 63–76. [Google Scholar]
  71. Erikson, K.M.; Jones, B.C.; Hess, E.J.; Zhang, Q.; Beard, J.L. Iron deficiency decreases dopamine D 1 and D 2 receptors in rat brain. Pharmacol. Biochem. Behav. 2001, 69, 409–418. [Google Scholar] [CrossRef]
  72. Chen, Q.; Connor, J.R.; Beard, J.L. Brain Iron, Transferrin and Ferritin Concentrations Are Altered in Developing Iron-Deficient Rats. J. Nutr. 1995, 125, 1529–1535. [Google Scholar] [PubMed]
  73. Waldmeier, P.C.; Buchle, A.M.; Steulet, A.F. Inhibition of catechol-O-methyltransferase (COMT) as well as tyrosine and tryptophan hydroxylase by the orally active iron chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20), in rat brain in vivo. Biochem. Pharmacol. 1993, 45, 2417–2424. [Google Scholar] [CrossRef]
  74. Taneja, V.; Mishra, K.; Agarwal, K.N. Effect of early iron deficiency in rat on the gamma-aminobutyric acid shunt in brain. J. Neurochem. 1986, 46, 1670–1674. [Google Scholar] [CrossRef] [PubMed]
  75. Li, D. Effects of iron deficiency on iron distribution and gamma-aminobutyric acid (GABA) metabolism in young rat brain tissues. Hokkaido J. Med. Sci. 1998, 73, 215–225. [Google Scholar] [PubMed]
  76. Appel, S.H.; Zhao, W.; Beers, D.R.; Henkel, J.S. The Microglial-Motoneuron dialogue in ALS. Acta Myol. 2011, 30, 4. [Google Scholar] [PubMed]
  77. Sica, A.; Mantovani, A. Macrophage plasticity and polarization: In vivo veritas. J. Clin. Investig. 2012, 122, 787–795. [Google Scholar] [CrossRef] [PubMed]
  78. Farber, N.B.; Kim, S.H.; Dikranian, K.; Jiang, X.P.; Heinkel, C. Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity. Mol. Psychiatry 2002, 7, 32–43. [Google Scholar] [CrossRef] [PubMed]
  79. Bai, N.; Aida, T.; Yanagisawa, M.; Katou, S.; Sakimura, K.; Mishina, M.; Tanaka, K. NMDA receptor subunits have different roles in NMDA-induced neurotoxicity in the retina. Mol. Brain 2013, 6, 34. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Franca-Costa, J.; Van Weyenbergh, J.; Boaventura, V.S.; Luz, N.F.; Malta-Santos, H.; Oliveira, M.C.; Santos de Campos, D.C.; Saldanha, A.C.; dos-Santos, W.L.; Bozza, P.T.; et al. Arginase I, polyamine, and prostaglandin E2 pathways suppress the inflammatory response and contribute to diffuse cutaneous leishmaniasis. J. Infect. Dis. 2015, 211, 426–435. [Google Scholar] [CrossRef] [PubMed]
  81. Wes, P.D.; Holtman, I.R.; Boddeke, E.W.; Moller, T.; Eggen, B.J. Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease. Glia 2016, 64, 197–213. [Google Scholar] [CrossRef] [PubMed]
  82. Butovsky, O.; Jedrychowski, M.P.; Moore, C.S.; Cialic, R.; Lanser, A.J.; Gabriely, G.; Koeglsperger, T.; Dake, B.; Wu, P.M.; Doykan, C.E.; et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 2014, 17, 131–143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Hickman, S.E.; Kingery, N.D.; Ohsumi, T.; Borowsky, M.; Wang, L.-C.; Means, T.K.; Khoury, J.E. The Microglial Sensome Revealed by Direct RNA Sequencing. Nat. Neurosci. 2013, 16, 1896–1905. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Chiu, I.M.; Morimoto, E.T.A.; Goodarzi, H.; Liao, J.T.; O’Keeffe, S.; Phatnani, H.P.; Muratet, M.; Carroll, M.C.; Levy, S.; Tavazoie, S.; et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013, 4, 385–401. [Google Scholar] [CrossRef] [PubMed]
  85. Wessling-Resnick, M. Iron homeostasis and the inflammatory response. Annu. Rev. Nutr. 2010, 30, 105–122. [Google Scholar] [CrossRef] [PubMed]
  86. Xu, H.; Wang, Y.; Song, N.; Wang, J.; Jiang, H.; Xie, J. New Progress on the Role of Glia in Iron Metabolism and Iron-Induced Degeneration of Dopamine Neurons in Parkinson’s Disease. Front. Mol. Neurosci. 2018, 10, 455. [Google Scholar] [CrossRef] [PubMed]
  87. Wang, J.; Song, N.; Jiang, H.; Wang, J.; Xie, J. Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons. Biochim. Biophys. Acta 2013, 1832, 618–625. [Google Scholar] [CrossRef] [PubMed]
  88. Kaur, C.; Ling, E.A. Increased expression of transferrin receptors and iron in amoeboid microglial cells in postnatal rats following an exposure to hypoxia. Neurosci. Lett. 1999, 262, 183–186. [Google Scholar] [CrossRef]
  89. Urrutia, P.; Aguirre, P.; Esparza, A.; Tapia, V.; Mena, N.P.; Arredondo, M.; Gonzalez-Billault, C.; Nunez, M.T. Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells. J. Neurochem. 2013, 126, 541–549. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Holland, R.; McIntosh, A.L.; Finucane, O.M.; Mela, V.; Rubio-Araiz, A.; Timmons, G.; McCarthy, S.A.; Gun’ko, Y.K.; Lynch, M.A. Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice. Brain Behav. Immun. 2018, 68, 183–196. [Google Scholar] [CrossRef] [PubMed]
  91. Gaasch, J.A.; Lockman, P.R.; Geldenhuys, W.J.; Allen, D.D.; Van der Schyf, C.J. Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells. Neurochem. Res. 2007, 32, 1196–1208. [Google Scholar] [CrossRef] [PubMed]
  92. Wessling-Resnick, M. Crossing the Iron Gate: Why and How Transferrin Receptors Mediate Viral Entry. Annu. Rev. Nutr. 2018, 38, 431–458. [Google Scholar] [CrossRef] [PubMed]
  93. Tanzi, R.E. The Genetics of Alzheimer Disease. Cold Spring Harb. Perspect. Med. 2012, 2, a006296. [Google Scholar] [CrossRef] [PubMed]
  94. Belaidi, A.A.; Bush, A.I. Iron neurochemistry in Alzheimer’s disease and Parkinson’s disease: Targets for therapeutics. J. Neurochem. 2016, 139, 179–197. [Google Scholar] [CrossRef] [PubMed]
  95. Praticò, D. Oxidative stress hypothesis in Alzheimer’s disease: A reappraisal. Trends Pharmacol. Sci. 2008, 29, 609–615. [Google Scholar] [CrossRef] [PubMed]
  96. Lane, D.J.R.; Ayton, S.; Bush, A.I. Iron and Alzheimer’s Disease: An Update on Emerging Mechanisms. J. Alzheimers Dis. 2018, 64, S379–S395. [Google Scholar] [CrossRef] [PubMed]
  97. Reddy, K.; Cusack, C.L.; Nnah, I.C.; Khayati, K.; Saqcena, C.; Huynh, T.B.; Noggle, S.A.; Ballabio, A.; Dobrowolski, R. Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency. Cell Rep. 2016, 14, 2166–2179. [Google Scholar] [CrossRef] [PubMed]
  98. Smith, C.D.; Carney, J.M.; Starke-Reed, P.E.; Oliver, C.N.; Stadtman, E.R.; Floyd, R.A.; Markesbery, W.R. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc. Natl. Acad. Sci. USA 1991, 88, 10540–10543. [Google Scholar] [CrossRef] [PubMed]
  99. Mecocci, P.; MacGarvey, U.; Beal, M.F. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann. Neurol. 1994, 36, 747–751. [Google Scholar] [CrossRef] [PubMed]
  100. Good, P.F.; Werner, P.; Hsu, A.; Olanow, C.W.; Perl, D.P. Evidence for Neuronal Oxidative Damage in Alzheimer’s Disease. Am. J. Pathol. 1996, 149, 21–28. [Google Scholar] [PubMed]
  101. Lovell, M.A.; Ehmann, W.D.; Butler, S.M.; Markesbery, W.R. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 1995, 45, 1594–1601. [Google Scholar] [CrossRef] [PubMed]
  102. Zhu, X.; Su, B.; Wang, X.; Smith, M.A.; Perry, G. Causes of oxidative stress in Alzheimer disease. Cell. Mol. Life Sci. 2007, 64, 2202–2210. [Google Scholar] [CrossRef] [PubMed]
  103. Bonda, D.J.; Wang, X.; Perry, G.; Nunomura, A.; Tabaton, M.; Zhu, X.; Smith, M.A. Oxidative stress in Alzheimer disease: A possibility for prevention. Neuropharmacology 2010, 59, 290–294. [Google Scholar] [CrossRef] [PubMed]
  104. Bush, A.I. The metal theory of Alzheimer’s disease. J. Alzheimers Dis. 2013, 33 (Suppl. 1), S277–S281. [Google Scholar] [CrossRef] [PubMed]
  105. Zeineh, M.M.; Chen, Y.; Kitzler, H.H.; Hammond, R.; Vogel, H.; Rutt, B.K. Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiol. Aging 2015, 36, 2483–2500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Filomeni, G.; Bolaños, J.P.; Mastroberardino, P.G. Redox Status and Bioenergetics Liaison in Cancer and Neurodegeneration. Int. J. Cell Biol. 2012, 2012, 659645. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Di Paolo, G.; Kim, T.-W. Linking lipids to Alzheimer’s disease: Cholesterol and beyond. Nat. Rev. Neurosci. 2011, 12, 284–296. [Google Scholar] [CrossRef] [PubMed]
  108. Peters, D.G.; Pollack, A.N.; Cheng, K.C.; Sun, D.; Saido, T.; Haaf, M.P.; Yang, Q.X.; Connor, J.R.; Meadowcroft, M.D. Dietary lipophilic iron alters amyloidogenesis and microglial morphology in Alzheimer’s disease knock-in APP mice. Metallomics 2018, 10, 426–443. [Google Scholar] [CrossRef] [PubMed]
  109. Yu, J.; Guo, Y.; Sun, M.; Li, B.; Zhang, Y.; Li, C. Iron is a potential key mediator of glutamate excitotoxicity in spinal cord motor neurons. Brain Res. 2009, 1257, 102–107. [Google Scholar] [CrossRef] [PubMed]
  110. Yang, W.S.; Stockwell, B.R. Ferroptosis: Death by Lipid Peroxidation. Trends Cell. Biol. 2016, 26, 165–176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Heneka, M.T.; Carson, M.J.; Khoury, J.E.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015, 14, 388–405. [Google Scholar] [CrossRef]
  112. El Khoury, J.B.; Moore, K.J.; Means, T.K.; Leung, J.; Terada, K.; Toft, M.; Freeman, M.W.; Luster, A.D. CD36 mediates the innate host response to beta-amyloid. J. Exp. Med. 2003, 197, 1657–1666. [Google Scholar] [CrossRef] [PubMed]
  113. Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.-C.; et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013, 493, 674–678. [Google Scholar] [CrossRef] [PubMed]
  114. Guerreiro, R.; Wojtas, A.; Bras, J.; Carrasquillo, M.; Rogaeva, E.; Majounie, E.; Cruchaga, C.; Sassi, C.; Kauwe, J.S.K.; Younkin, S.; et al. Alzheimer Genetic Analysis Group, T.A.G.A. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 2013, 368, 117–127. [Google Scholar] [CrossRef] [PubMed]
  115. Atagi, Y.; Liu, C.-C.; Painter, M.M.; Chen, X.-F.; Verbeeck, C.; Zheng, H.; Li, X.; Rademakers, R.; Kang, S.S.; Xu, H.; et al. Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). J. Biol. Chem. 2015, 290, 26043–26050. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Bailey, C.C.; DeVaux, L.B.; Farzan, M. The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E. J. Biol. Chem. 2015, 290, 26033–26042. [Google Scholar] [CrossRef] [PubMed]
  117. Wang, Y.; Cella, M.; Mallinson, K.; Ulrich, J.D.; Young, K.L.; Robinette, M.L.; Gilfillan, S.; Krishnan, G.M.; Sudhakar, S.; Zinselmeyer, B.H.; et al. TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model. Cell 2015, 160, 1061–1071. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Yeh, F.L.; Wang, Y.; Tom, I.; Gonzalez, L.C.; Sheng, M. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron 2016, 91, 328–340. [Google Scholar] [CrossRef] [PubMed]
  119. Yuan, P.; Condello, C.; Keene, C.D.; Wang, Y.; Bird, T.D.; Paul, S.M.; Luo, W.; Colonna, M.; Baddeley, D.; Grutzendler, J. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron 2016, 90, 724–739. [Google Scholar] [CrossRef] [PubMed]
  120. Jay, T.R.; Hirsch, A.M.; Broihier, M.L.; Miller, C.M.; Neilson, L.E.; Ransohoff, R.M.; Lamb, B.T.; Landreth, G.E. Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease. J. Neurosci. 2017, 37, 637–647. [Google Scholar] [CrossRef] [PubMed]
  121. Ulland, T.K.; Song, W.M.; Huang, S.C.-C.; Ulrich, J.D.; Sergushichev, A.; Beatty, W.L.; Loboda, A.A.; Zhou, Y.; Cairns, N.J.; Kambal, A.; et al. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease. Cell 2017, 170, 649–663. [Google Scholar] [CrossRef] [PubMed]
  122. Zhao, Y.; Wu, X.; Li, X.; Jiang, L.L.; Gui, X.; Liu, Y.; Sun, Y.; Zhu, B.; Pina-Crespo, J.C.; Zhang, M.; et al. TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function. Neuron 2018, 97, 1023–1031. [Google Scholar] [CrossRef] [PubMed]
  123. Hyman, B.T.; Holtzman, D.M. Apolipoprotein E levels and Alzheimer risk. Ann. Neurol. 2015, 77, 204–205. [Google Scholar] [CrossRef] [PubMed]
  124. Terwel, D.; Steffensen, K.R.; Verghese, P.B.; Kummer, M.P.; Gustafsson, J.-A.; Holtzman, D.M.; Heneka, M.T. Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis. J. Neurosci. 2011, 31, 7049–7059. [Google Scholar] [CrossRef] [PubMed]
  125. Cammer, W. Oligodendrocyte-Associated Enzymes. In Oligodendroglia. Advances in Neurochemistry; William, N., Ed.; Springer: Boston, MA, USA, 1984; pp. 199–232. [Google Scholar]
  126. Xu, Q.; Li, Y.; Cyras, C.; Sanan, D.A.; Cordell, B. Isolation and characterization of apolipoproteins from murine microglia. Identification of a low density lipoprotein-like apolipoprotein J-rich but E-poor spherical particle. J. Biol. Chem. 2000, 275, 31770–31777. [Google Scholar] [CrossRef] [PubMed]
  127. Cudaback, E.; Li, X.; Montine, K.S.; Montine, T.J.; Keene, C.D. Apolipoprotein E isoform-dependent microglia migration. FASEB J. 2011, 25, 2082–2091. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Mandrekar-Colucci, S.; Karlo, J.C.; Landreth, G.E. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J. Neurosci. 2012, 32, 10117–10128. [Google Scholar] [CrossRef] [PubMed]
  129. Ayton, S.; Faux, N.G.; Bush, A.I. Alzheimer’s Disease Neuroimaging Initiative, A.s.D.N. Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat. Commun. 2015, 6, 6760. [Google Scholar] [CrossRef] [PubMed]
  130. Ali-Rahmani, F.; Schengrund, C.-L.; Connor, J.R. HFE gene variants, iron, and lipids: A novel connection in Alzheimer’s disease. Front. Pharmacol. 2014, 5, 165. [Google Scholar] [CrossRef] [PubMed]
  131. McLachlan, D.R.C.; Kruck, T.P.A.; Kalow, W.; Andrews, D.F.; Dalton, A.J.; Bell, M.Y.; Smith, W.L. Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 1991, 337, 1304–1308. [Google Scholar] [CrossRef]
  132. Palanimuthu, D.; Poon, R.; Sahni, S.; Anjum, R.; Hibbs, D.; Lin, H.Y.; Bernhardt, P.V.; Kalinowski, D.S.; Richardson, D.R. A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer’s disease. Eur. J. Med. Chem. 2017, 139, 612–632. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Iron and mitochondrial function. The mitochondrial electron transport chain contains multiple iron–sulfur clusters and heme-containing proteins necessary for ATP synthesis. NADH dehydrogenase (complex I) contains eight Fe–S clusters, succinate dehydrogenase (complex II) contains three Fe–S clusters and one heme moiety, while complex III (cytochrome bc1) contains one Fe–S cluster and several heme groups vital for its functions. Complex IV (cytochrome c oxidase) also contains two heme moieties. Aconitase, a key enzyme that catalyzes the stereo-specific isomerization of citrate to isocitrate through cis-aconitate in the tricarboxylic acid (TCA) cycle contain Fe–S clusters.
Figure 1. Iron and mitochondrial function. The mitochondrial electron transport chain contains multiple iron–sulfur clusters and heme-containing proteins necessary for ATP synthesis. NADH dehydrogenase (complex I) contains eight Fe–S clusters, succinate dehydrogenase (complex II) contains three Fe–S clusters and one heme moiety, while complex III (cytochrome bc1) contains one Fe–S cluster and several heme groups vital for its functions. Complex IV (cytochrome c oxidase) also contains two heme moieties. Aconitase, a key enzyme that catalyzes the stereo-specific isomerization of citrate to isocitrate through cis-aconitate in the tricarboxylic acid (TCA) cycle contain Fe–S clusters.
Pharmaceuticals 11 00129 g001
Figure 2. Iron trafficking and microglial cell polarization. (Left) Pro-inflammatory stimuli upregulate the expression of divalent metal transporter-1 (DMT-1) and the uptake of non-Tf-bound iron (NTBI). These effects are associated with increased labile iron and an expanded pool of ferritin. These changes reflect M1 polarization. (Right) Anti-inflammatory stimuli increase transferrin receptor (TfR) levels to upregulate Tf-bound iron (TBI) uptake by receptor-mediated endocytosis. In recycling endosomes, the low pH promotes the release of Fe3+ for ferrireduction, most likely by STEAP3. Fe2+ may be released into the cytosol through DMTI or another channel for use in mitochondria to promote heme production. We speculate that, under anti-inflammatory conditions, microglia may release ferritin (Ftn)-bound iron through lysosomal exocytosis to help oligodendrocyte function and neuronal repair.
Figure 2. Iron trafficking and microglial cell polarization. (Left) Pro-inflammatory stimuli upregulate the expression of divalent metal transporter-1 (DMT-1) and the uptake of non-Tf-bound iron (NTBI). These effects are associated with increased labile iron and an expanded pool of ferritin. These changes reflect M1 polarization. (Right) Anti-inflammatory stimuli increase transferrin receptor (TfR) levels to upregulate Tf-bound iron (TBI) uptake by receptor-mediated endocytosis. In recycling endosomes, the low pH promotes the release of Fe3+ for ferrireduction, most likely by STEAP3. Fe2+ may be released into the cytosol through DMTI or another channel for use in mitochondria to promote heme production. We speculate that, under anti-inflammatory conditions, microglia may release ferritin (Ftn)-bound iron through lysosomal exocytosis to help oligodendrocyte function and neuronal repair.
Pharmaceuticals 11 00129 g002

Share and Cite

MDPI and ACS Style

Nnah, I.C.; Wessling-Resnick, M. Brain Iron Homeostasis: A Focus on Microglial Iron. Pharmaceuticals 2018, 11, 129.

AMA Style

Nnah IC, Wessling-Resnick M. Brain Iron Homeostasis: A Focus on Microglial Iron. Pharmaceuticals. 2018; 11(4):129.

Chicago/Turabian Style

Nnah, Israel C., and Marianne Wessling-Resnick. 2018. "Brain Iron Homeostasis: A Focus on Microglial Iron" Pharmaceuticals 11, no. 4: 129.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop