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Neurotherapeutics

, Volume 15, Issue 4, pp 1055–1062 | Cite as

Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice

  • Abdel A. Belaidi
  • Adam P. Gunn
  • Bruce X. Wong
  • Scott Ayton
  • Ambili T. Appukuttan
  • Blaine R. Roberts
  • James A. Duce
  • Ashley I. Bush
Original Article

Abstract

Proteolytic cleavage of the amyloid precursor protein (APP) into the Aβ peptide has been an extensively researched mechanism for Alzheimer’s disease, but the normal function of the protein is less understood. APP functions to regulate neuronal iron content by stabilizing the surface presentation of ferroportin—the only iron exporter channel of cells. The present study aims to quantify the contribution of APP to brain and peripheral iron by examining the lifetime impact on brain and liver iron levels in APP knockout mice. Consistent with previous reports, we found that wild-type mice exhibited an age-dependent increase in iron and ferritin in the brain, while no age-dependent changes were observed in the liver. APP ablation resulted in an exaggeration of age-dependent iron accumulation in the brain and liver in mice that was assessed at 8, 12, 18, and 22 months of age. Brain ferroportin levels were decreased in APP knockout mice, consistent with a mechanistic role for APP in stabilizing this iron export protein in the brain. Iron elevation in the brain and liver of APP knockout mice correlated with decreased transferrin receptor 1 and increased ferritin protein levels. However, no age-dependent increase in brain ferritin iron saturation was observed in APP-KO mice despite similar protein expression levels potentially explaining the vulnerability of APP-KO mice to parkinsonism and traumatic brain sequelae. Our results support a crucial role of APP in regulating brain and peripheral iron, and show that APP may act to oppose brain iron elevation during aging.

Keywords

Amyloid precursor protein Iron Ferritin Brain Neurodegeneration 

Notes

Acknowledgments

Support by the National Health and Medical Council of Australia (NHMRC), the Australian Research Council, and the German Research Foundation (DFG: BE 5471/1-1 to AAB) is gratefully acknowledged.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Compliance with Ethical Standards

All mouse studies were performed with the approval of the IACUC and in accordance with statutory regulations.

Conflict of Interest

BR receives research support for Agilent. AIB is a shareholder in Prana Biotechnology Ltd., Cogstate Ltd., Brighton Biotech LLC, Grunbiotics Pty Ltd., Eucalyptus Pty Ltd., and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd.

Supplementary material

13311_2018_656_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1225 kb)

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  1. 1.Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  2. 2.Alzheimer’s Research UK Cambridge Drug Discovery InstituteUniversity of CambridgeCambridgeUK

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