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Iron, brain ageing and neurodegenerative disorders

Nature Reviews Neuroscience volume 5, pages 863–873 (2004)Cite this article

Key Points

  • Iron is an essential cofactor for many proteins that are involved in normal neuronal tissue function, but there is increasing evidence that iron accumulation in the brain can cause a vast array of CNS disorders.

  • Global iron homeostasis is regulated at the level of iron absorption from the gastrointestinal tract. This involves a series of molecular interactions between proteins that include the haemochromatosis gene product HFE, transferrin, the transferrin receptor and iron regulatory proteins in the crypts of Lieberkühn.

  • The brain has several characteristics that make it unique with regard to iron metabolism. It resides behind a vascular barrier — the blood–brain barrier — which limits its access to plasma iron. Also, the concentration of iron varies considerably between different brain regions: regions that are associated with motor functions tend to have more iron than non-motor-related regions.

  • Iron seems to accumulate in the brain as a function of age. This process is quite specific, and it involves the accumulation of iron-containing molecules in certain cell types, particularly in brain regions that are preferentially targeted in neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD).

  • PD is associated with increased iron accumulation in the substantia nigra. Proposed mechanisms for iron-induced cell damage in PD include enhanced generation of reactive oxygen species and an increase in oxidative stress and protein aggregation. This includes the aggregation of α-synuclein, which is one of the main components of Lewy bodies — one of the pathological hallmarks of PD.

  • In AD, iron accumulation in the brain occurs without the normal age-related increase in ferritin, and this increases the risk of oxidative stress. Iron might also have a direct impact on plaque formation through its effects on amyloid precursor protein processing.

  • Iron accumulation has also been implicated in several other neurological diseases, including congenital aceruloplasminaemia, Friedreich's ataxia, neuroferritinopathy, neurodegeneration with brain iron accumulation and restless legs syndrome.

  • Metal chelators are being developed as a new therapeutic strategy for the treatment of PD, AD and other neurodegenerative disorders that involve iron misregulation.

  • If we can understand the timing of iron mismanagement in relation to the progression of neuronal loss in neurodegenerative diseases and during ageing, this might raise the possibility of monitoring iron changes as a marker of disease progression, and perhaps even pre-clinical diagnosis in conditions where iron mismanagement is an early event.

Abstract

There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases. Conditions such as neuroferritinopathy and Friedreich ataxia are associated with mutations in genes that encode proteins that are involved in iron metabolism, and as the brain ages, iron accumulates in regions that are affected by Alzheimer's disease and Parkinson's disease. High concentrations of reactive iron can increase oxidative-stress induced neuronal vulnerability, and iron accumulation might increase the toxicity of environmental or endogenous toxins. By studying the accumulation and cellular distribution of iron during ageing, we should be able to increase our understanding of these neurodegenerative disorders and develop new therapeutic strategies.

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Figure 1: The Tf cycle.
Figure 2: Translational regulation of the transferrin receptor and ferritin production.
Figure 3: Iron deposits in the ageing brain.
Figure 4: Iron and oxidative stress hypothesis of Parkinson's disease.
Figure 5: Haemochromatosis protein staining of reactive astrocytes in brains of patients with Alzheimer's disease.
Figure 6: Iron-induced neurodegeneration in Parkinson's disease and its prevention.

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Acknowledgements

The authors thank C. Bellei for skillful assistance. M.B.H.Y. was supported by the National Parkinson Foundation (Miami, Florida, USA). M.B.H.Y. and L.Z. acknowledge the support of the Michael J. Fox Foundation (New York, USA). L.Z. was also supported by the Italian Fund for Basic Science (FIRB-MIUR) and the Parkinson's Disease Foundation (New York, USA). J.R.C. acknowledges the support of the Alzheimer's Association, the National Institutes of Health, the Jane B. Barsumian Trust Fund and the G.M. Leader Family.

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Authors and Affiliations

  1. Institute of Biomedical Technologies-Italian National Research Council, Segrate (Milano), 20090, Italy

    Luigi Zecca

  2. Technion-Rappaport Faculty of Medicine and Rappaport Institute, Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Haifa, Israel

    Moussa B. H. Youdim

  3. Clinical Neurochemistry and US National Parkinson Foundation Center, Clinic for Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

    Peter Riederer

  4. Penn State College of Medicine, M.S. Hershey Medical Center, Hershey, Pennsylvania, USA

    James R. Connor

  5. Unit of Biochemistry, Catholic University of Louvain, Louvain-la-Neuve, Belgium

    Robert R. Crichton

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  1. Luigi Zecca
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  3. Peter Riederer
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Correspondence to Luigi Zecca.

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Competing interests

M.B.H.Y. has financial interests in Varinel Inc. (Philadelphia, USA) — the company that is developing the iron chelators VK-28, HLA and M30 — and in Teva Pharmaceutical Industries Ltd (Israel), which is developing the Parkinson-therapeutic drug Rasagiline (and has received a letter of approval for this drug from the United States Food and Drug Administration). To date he has not received any financial reward from them. The other authors all have no competing financial interests.

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DATABASES

Entrez Gene

DCT1

DCYTB

HFE

IREG1

PANK2

TF

TFR

FURTHER INFORMATION

Encyclopedia of Life Sciences

Parkinson disease

Alzheimer disease

Glossary

HAEMOCHROMATOSIS

An iron-overload disorder, in which an excessive amount of iron is absorbed from the diet. The iron accumulates in various organs, including the liver, pancreas and heart, which can lead to severe organ damage.

ENDOSOMAL COMPARTMENT

A system of organelles that carry materials that have been ingested by endocytosis, and pass them to lysosomes for degradation, or recycle them to the cell surface.

MICROGLIA

Phagocytic immune cells in the brain that engulf and remove cells that have undergone apoptosis.

SUBSTANTIA NIGRA

A part of the midbrain that contains dopamine-producing neurons, the axons of which innervate the striatum and thereby control body movements.

LOCUS COERULEUS

A nucleus of the brainstem that is the main supplier of noradrenaline to the brain.

CHOROID PLEXUS

A site of production of cerebrospinal fluid in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.

PUTAMEN/CAUDATE NUCLEUS

Two of the components of the striatum, a subpallidal structure that also includes the nucleus accumbens and the olfactory tubercle.

GLOBUS PALLIDUS

The medial part of the lentiform nucleus, which is one of the components of the basal ganglia.

LEWY BODIES

Intraneuronal inclusion bodies that form one of the pathological hallmarks of Parkinson's disease. They consist of a dense granular core that is surrounded by a halo of radiating filaments. Their main protein components include α-synuclein and ubiquitin.

UBIQUITIN

A molecule that is attached to lysine residues of other proteins, often as a tag for their rapid cellular degradation by the proteasome.

REACTIVE OXYGEN SPECIES

(ROS) Oxygen radicals that are produced by the mitochondrial respiratory chain. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death.

TAU

A neuronal protein that binds to microtubules, promoting their assembly and stability. It is also a component of neurofibrillary tangles, which are one of the pathological hallmarks of Alzheimer's disease.

DYSTONIA

A movement disorder that is characterized by abnormal muscle tone.

WILSON'S DISEASE

A genetic disorder that causes excessive copper accumulation in the liver and brain, resulting in hepatitis and psychiatric and neurological symptoms.

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Zecca, L., Youdim, M., Riederer, P. et al. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5, 863–873 (2004). https://doi.org/10.1038/nrn1537

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