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Acta Neuropathologica Communications

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Open Access 01-12-2013 | Research

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

Authors: Animesh Alexander Raha, Radhika Anand Vaishnav, Robert Paul Friedland, Adrian Bomford, Ruma Raha-Chowdhury

Published in: Acta Neuropathologica Communications | Issue 1/2013

Abstract

Background

The pathological features of the common neurodegenerative conditions, Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse.

Results

Protein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels.

Conclusion

Our results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons.

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Title: The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease
Authors: Animesh Alexander Raha
Radhika Anand Vaishnav
Robert Paul Friedland
Adrian Bomford
Ruma Raha-Chowdhury
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2013
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/2051-5960-1-55

At a glance: The STEP trials

Springer Medicine

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

Abstract

Background

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusion

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