The role of iron in brain ageing and neurodegenerative disorders

Summary

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.

Introduction

Iron is involved in many fundamental biological processes in the brain including oxygen transportation, DNA synthesis, mitochondrial respiration, myelin synthesis, and neurotransmitter synthesis and metabolism.¹ Iron homoeostasis is needed to maintain normal physiological brain function, whereas misregulation of iron homoeostasis can cause neurotoxicity through different mechanisms. Homoeostatic mechanisms provide the conditions for optimum cell function by maintaining an equilibrium of available iron concentrations between cellular compartments and buffering molecules, and preventing toxic effects caused by excessive concentrations of free iron.2, 3 When iron concentrations exceed the cellular iron sequestration capacity of storage proteins or other molecules, the concentration of iron in the labile iron pool (panel) can increase, which could be harmful and lead to oxidative damage and cell death.⁴

In healthy ageing, selective accumulation of iron occurs in several brain regions and cell types, with iron mainly bound within ferritin and neuromelanin (panel).5, 6 However, the accumulation of iron in specific brain regions, greater than that reported in healthy ageing, occurs in many neurodegenerative diseases and is often associated with oxidative stress and cellular damage. Whether the iron accumulation noted in neurodegenerative diseases is a primary event or a secondary effect is unclear. Ageing is the major risk factor for neurodegeneration. Age-related accumulation of iron might be an important factor that contributes to neurodegenerative processes.

The development of diagnostic and therapeutic strategies involves the use of disease-specific animal models and non-invasive imaging approaches, such as MRI and ultrasound imaging (sonography). In this Review, we discuss the cellular and molecular distribution of iron in healthy brains as they age, summarising factors that might be responsible for age-dependent increases of iron in different areas of the human brain; dysregulation of iron homeostasis in prevalent neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis; iron accumulation in less prevalent disorders such as Friedreich's ataxia, aceruloplasminaemia and neuroferritinopathy (both categorically referred to as neurodegeneration with brain iron accumulation), Huntington's disease, and restless legs syndrome; the use of iron chelators as a potential therapy for the aforementioned diseases and disorders; and finally, discuss advances in mapping brain iron distributions with high-field MRI.