The Aging of Iron Man

Abstract

Brain iron is tightly regulated by a multitude of proteins to ensure homeostasis. Iron dyshomeostasis has become a molecular signature associated with aging which is accompanied by progressive decline in cognitive processes. A common theme in neurodegenerative diseases where age is the major risk factor, iron dyshomeostasis coincides with neuroinflammation, abnormal protein aggregation, neurodegeneration, and neurobehavioral deficits. There is a great need to determine the mechanisms governing perturbations in iron metabolism, in particular to distinguish between physiological and pathological aging to generate fruitful therapeutic targets for neurodegenerative diseases. The aim of the present review is to focus on the age-related alterations in brain iron metabolism from a cellular and molecular biology perspective, alongside genetics, and neuroimaging aspects in man and rodent models, with respect to normal aging and neurodegeneration. In particular, the relationship between iron dyshomeostasis and neuroinflammation will be evaluated, as well as the effects of systemic iron overload on the brain. Based on the evidence discussed here, we suggest a synergistic use of iron-chelators and anti-inflammatories as putative anti-brain aging therapies to counteract pathological aging in neurodegenerative diseases.

Keywords: Alzheimer's disease; Parkinson's disease; aging; brain iron; iron overload; iron regulation; neurodegenerative diseases; neuroinflammation.

Figure 1

Systemic iron regulation. Iron-loaded apo-transferrin (Apo-Tf) forms holo-Tf and binds to Tf receptor-1 (TfR1) on the intestinal membrane and the holo-Tf/TfR1complex is endocytosed via clathrin-coated pits (Lambe et al., ; Duck and Connor, 2016). STEAP3 reduces the ferric iron (Fe³⁺) to ferrous iron (Fe²⁺) in the endosome and Fe²⁺ is transported into cytosol by divalent metal transporter-1 (DMT1), contributing to the labile iron pool. The apo-Tf/TfR1 complex is recycled to the cell membrane, where apo-Tf is released to bind to circulating plasma Fe³⁺. The excess iron is either sequestrated by ferritin or exported out of the cell by ferroportin (Fpn), in association with hephaestin (Heph). Hepcidin binds to Fpn mediating Fpn internalization and degradation, thereby preventing dietary iron absorption, dependent on the body iron status (Ganz, 2013).

Figure 2

Schematic of the transportation of iron across the blood brain barrier (BBB) and into the brain. Apo-transferrin (Apo-Tf) binds to ferric iron (Fe³⁺) in the systemic circulation to form holo-Tf (Ke et al., ; Moos et al., ; Leitner and Connor, 2012). The BBB, formed by tight junctions between brain vascular endothelial cells (BVECs), limits transport of materials from the blood into the brain. Systemic holo-Tf binds to the Tf receptor-1 (TfR1) located on the luminal (blood) side (BVECs), and the newly formed holo-Tf/TfR1 complex is internalized into BVECs. Endosomal ferri-reductase catalyzes the reduction of Fe³⁺ to ferrous iron (Fe²⁺), enabling Fe²⁺ export into the cytosol from the endosome possibly through divalent metal transporter-1 (DMT1). At the abluminal (brain) side, the cellular Fe²⁺ enters the interstitium through an iron exporter, ferroportin, aided by rapid oxidation of Fe²⁺ to Fe³⁺ by ferroxidases (ceruloplasmin, hephaestin). The expression of polarized DMT1 in astrocytic foot-processes from close associations with BVECs, may facilitate rapid uptake of Fe²⁺ following their release into the perivascular space of the brain (Ward et al., 2014). Neurons can influx iron via a holo-Tf/TfR1-dependent uptake mechanism. In contrast, detectable levels of TfR1 are not expressed by either astrocytes nor oligodendrocytes. Tim-2, a ferritin receptor (Han et al., 2011), aids in oligodendrocyte iron uptake while non-Tf bound iron is taken up via DMT1.

Figure 3

Neuro-vascular unit and the glymphatic pathway. The neuro-vascular unit (A) regulates transport into the brain and the glymphatic pathway enables communication between the microvasculature and neurons, with astrocytes acting as intermediators (B). The CSF enters the brain parenchyma along paravascular spaces surrounding the penetrating arteries (Virchow-Robin space) exchanges with the brain interstitial fluid (Iliff et al., 2012, 2013) that bathes the brain (red arrow B; para-arterial CSF influx route). Interstitial solutes are subsequently cleared to paravascular spaces located in the vicinity of large caliber draining veins (purple arrow; para-venous interstitial fluid clearance route). The trans-parenchymal pathway (green arrow) allows convective bulk flow between the paravascular CSF influx and interstitial fluid efflux pathways facilitated by the exclusive perivascular astrocytic end-feet expressed aquaporin-4 (Aqp4) water channels (Nielsen et al., ; Mathiisen et al., 2010). This convective bulk flow mediates clearance of the interstitial solutes from the brain.

Figure 4

Overview of cellular metabolism of iron in the brain. Transferrin (Tf) laden with iron (holo-Tf) binds to the Tf receptor-1 (TfR1), and iron enters the cell by receptor-mediated endocytosis and into endosomes (Moos and Morgan, ; Moos et al., 2007). Iron can be released from endosomes into the cytosolic labile iron pool, from here, iron can either be utilized in cellular processes or stored in ferritin (Ward et al., 2014). Additionally, ferrous iron (Fe²⁺) may enter cells via divalent metal transporter-1 (DMT1) into the cytosolic labile iron pool, but only a relatively small amount of ferrous iron is transported by this way. Excess Fe²⁺ may also be exported from the cell by ferroportin (Fpn), aided by membrane-bound ferroxidase ceruloplasmin (only present in astrocytes) (De Domenico et al., 2007). Ceruloplasmin is not known to regulate the Fpn-mediated export but stabilizes Fpn. Ferroxidases (hephaestin and ceruloplasmin) in the circulation or the cell surface oxidize Fe²⁺ to ferric (Fe³⁺) iron and facilitates binding to apo-Tf to form holo-Tf for vasculature transport. Hepcidin in the extracellular space inhibits iron export by binding to Fpn and mediates Fpn internalization and degradation (Ganz and Nemeth, 2012). The extracellular iron status modulates the cellular hepcidin levels by interactions between TfR1 and HFE TfR1which in turn regulates cellular hepcidin levels via unknown mechanisms. The key proteins involved in peripheral and central iron homeostasis are similar. However, the brain has its own unique regulatory mechanisms, as it is isolated by the cellular barriers–the blood brain and blood-CSF barriers. The exact way in which the different brain cell types interact with one another to maintain iron homeostasis remains to be elucidated. Also, the mechanism underlying the cross-talk between the brain and the periphery to regulate global iron homeostasis is not fully characterized.

Figure 5

IRE/IRP regulation of ferritin and transferrin receptor. Proteins involved in the storage, export and uptake of iron are regulated via the interaction of iron-regulatory proteins (IRPs) with iron-responsive element (IREs), conserved RNA secondary structures (Rouault, ; Leipuviene and Theil, 2007). In conditions of low iron, IRP binds to a single IRE in the 5′-untranslated region (UTR) of ferritin mRNA to suppress their translation, while IRP binding to multiple IREs in the 3′ UTR of transferrin receptor-1 (TfR1) which stabilizes the mRNA for TfR1 synthesis. When the iron content in the cell is high, the lack of IRP-binding leads to increased synthesis of ferritin and destabilization of TfR1 mRNA.