The role of iron in brain ageing and neurodegenerative disorders

Abstract

In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbohydrates, and DNA. During ageing, different iron complexes accumulate in brain regions associated with motor and cognitive impairment. In various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in iron homoeostasis result in altered cellular iron distribution and accumulation. MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases. An important avenue to reduce iron accumulation is the use of iron chelators that are able to cross the blood-brain barrier, penetrate cells, and reduce excessive iron accumulation, thereby affording neuroprotection.

Figure 1. Brain iron metabolism

Iron enters the endothelial cells of the blood–brain barrier as a low molecular weight complex, or via transferrin receptor-1 mediated endocytosis of transferrin, or independently as non-transferrin-bound iron.^– Transferrin receptors line the lumen of the brain and bind circulating differic–transferrin facilitating iron uptake into brain vascular endothelial cells via receptor–mediated endocytosis. Whether there is a DMT1–ferroportin-independent pathway to release ferric iron or differic-transferrin by exocytosis of recycling endosomes is unclear (vesicular export pathway, left side in brain vascular endothelial cells). Transferrin is synthesised by the choroid plexus or oligodentrocytes so that any ferric iron released from the abluminal side of the endothelial cells can form complexes with transferrin or alternatively low molecular weight molecules (eg, ascorbate, citrate, or ATP) to form non-transferrin-bound iron. Citrate and ATP can be released from the astrocytes. Whether there is a DMT1–ferroportin-dependent (non-vesicular export, right side in brain vascular endothelial cells) pathway to release ferrous iron, which would be rapidly converted to ferric iron via ceruloplasmin in the abluminal membranes, is also unknown. The glycosylphosphatidylinositol-anchored form of ceruloplasmin is highly expressed by astrocytes in the mammalian CNS and is physically associated with ferroportin. Astrocytes are ideally positioned to take up iron from the circulation and distribute it to other cells in the CNS. Astrocytes have the iron influx and efflux mechanisms needed for cell-to-cell transport of iron. DMT1 is expressed by astrocytes and probably mediates iron influx into these glial cells. Iron can be stored as ferritin in astrocytes and exported by a mechanism that involves ferroportin and ceruloplasmin. Oligodentrocytes might take up iron via the ferritin receptor Tim-2, or non-transferrin-bound iron via DMT1, or other non-vesicular iron import mechanisms. Neurons and microglia can influx iron via transferrin–transferrin receptor mediated uptake and efflux iron via ferroportin. IRPs (1 and 2), DMT1, and −IRE DMT1 (non-IRE form of DMT1 protein) are expressed mostly by astrocytes. Increased iron regulatory proteins expression might lead to increased expression of the +IRE form of DMT1. The role of hepcidin in orchestrating the regulation of egress from cells via ferroportin in different brain cells remains unclear. Neuron axons are wrapped with the myelin sheath, which is made of oligodendrocytes in an iron-dependent manner. Microglia form an association with neurons via CD200/CD200R to maintain the quiescent state. Microglia might take up iron via transferrin receptor and release iron via ferroportin. Dashed lines represent unknown regulation of iron. Solid arrows show iron movement. Reproduced and adapted from Mills and colleagues, by permission of Future Science. BBB=blood–brain barrier. TFR=transferrin receptor. Tf=transferrin. Fe²⁺=ferrous iron. Fe³⁺=ferric iron. BVEC=brain vascular endothelial cells. Cp=ceruloplasmin. Fpn=ferroportin. DMT1=divalent metal ion transporter 1. Ft=ferritin. IRP=iron regulatory protein. IRE=iron responsive or regulatory element. Hepc=hepcidin. N=nucleus. MS=myelin sheath. ?=unknown pathway or mechanism. CD200=OX-2 membrane glycoprotein. CD200R=CD200 receptor.

Figure 2. MRI of iron in Parkinson’s disease

T₂*-weighted MRI of midbrain in a patient with early onset Parkinson’s disease. Substantia nigra and red nucleus, naturally high in iron, seem darker because of reduced T₂*. In Parkinson’s disease, further iron accumulations^, and morphological changes are seen in substantia nigra; both are associated with disability. Reproduced from Cho and colleagues by permission of John Wiley & Sons.

Figure 3. MRI detection of fine-scale spatial variation in iron content in healthy brain tissue

(A) Laminar variations shown in luxol fast blue myelin stain. Laminar patterns seem specific to functional areas V1 and V2. (B) Laminar patterns shown in Perls’ 3,3’-diaminobenzidine iron stain. (C) R2* (=1/T₂*) obtained from 7T post mortem MRI. The dashed line indicates calcarine sulcus. Solid arrows, open arrows, and arrowheads show areas of increased iron in central and deep layers, and subcortical white matter. Reproduced from Fukunaga and colleagues with permission of Proceedings of the National Academy of Sciences.