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Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats

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Abstract

Iron accumulates progressively in the brain with age, and iron-induced oxidative stress has been considered as one of the initial causes for Alzheimer’s disease (AD) and Parkinson’s disease (PD). Based on the role of hepcidin in peripheral organs and its expression in the brain, we hypothesized that this peptide has a role to reduce iron in the brain and hence has the potential to prevent or delay brain iron accumulation in iron-associated neurodegenerative disorders. Here, we investigated the effects of hepcidin expression adenovirus (ad-hepcidin) and hepcidin peptide on brain iron contents, iron transport across the brain–blood barrier, iron uptake and release, and also the expression of transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin 1 (Fpn1) in cultured microvascular endothelial cells and neurons. We demonstrated that hepcidin significantly reduced brain iron in iron-overloaded rats and suppressed transport of transferrin-bound iron (Tf-Fe) from the periphery into the brain. Also, the peptide significantly inhibited expression of TfR1, DMT1, and Fpn1 as well as reduced Tf-Fe and non-transferrin-bound iron uptake and iron release in cultured microvascular endothelial cells and neurons, while downregulation of hepcidin with hepcidin siRNA retrovirus generated opposite results. We concluded that, under iron-overload, hepcidin functions to reduce iron in the brain by downregulating iron transport proteins. Upregulation of brain hepcidin by ad-hepcidin emerges as a new pharmacological treatment and prevention for iron-associated neurodegenerative disorders.

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Abbreviations

AD:

Alzheimer’s disease

BMECs:

Brain microvascular endothelial cells

DMT1:

Divalent metal transporter 1

DMT1+IRE:

Divalent metal transporter 1 with iron response element

DMT1−IRE:

Divalent metal transporter 1 without iron response element

Fpn1:

Ferroportin 1

NTBI:

Non-transferrin-bound iron

PKAN:

Pantothenate kinase-associated neurodegeneration

PD:

Parkinson’s disease

Tf-Fe:

Transferrin-bound iron

TfR1:

Transferrin receptor

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Acknowledgments

The studies in our laboratories were supported the General Grant of National Natural Science Foundation of China (NSFC) (31271132, 31371092), by the Competitive Earmarked Grants of The Hong Kong Research Grants Council (GRF 466713), National 973 Programs (2011CB510004), and Key Project Grant of NSFC (31330035).

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai, 201203, People’s Republic of China

    Fang Du, Zhong-Ming Qian & Qianqian Luo

  2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong, People’s Republic of China

    Fang Du, Wing-Ho Yung & Ya Ke

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Correspondence to Zhong-Ming Qian or Ya Ke.

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Du, F., Qian, ZM., Luo, Q. et al. Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats. Mol Neurobiol 52, 101–114 (2015). https://doi.org/10.1007/s12035-014-8847-x

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