β-Amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin

Bruce X Wong; Andrew Tsatsanis; Linh Q Lim; Paul A Adlard; Ashley I Bush; James A Duce

doi:10.1371/journal.pone.0114174

β-Amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin

PLoS One. 2014 Dec 2;9(12):e114174. doi: 10.1371/journal.pone.0114174. eCollection 2014.

Authors

Bruce X Wong¹, Andrew Tsatsanis², Linh Q Lim³, Paul A Adlard⁴, Ashley I Bush⁴, James A Duce⁵

Affiliations

¹ Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
² School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, United Kingdom.
³ Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
⁴ Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
⁵ Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, United Kingdom; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.

Abstract

Ceruloplasmin is a ferroxidase that interacts with ferroportin to export cellular iron, but is not expressed in neurons. We recently reported that the amyloid precursor protein (APP) is the analogous iron-exporting chaperone for neurons and other cells. The ferroxidase activity of APP has since been called into question. Using a triplex Fe2+ oxidation assay, we analyzed the activity of a soluble form of APP (sAPPα) within a buffer of physiological pH and anionic charge, and determined that iron oxidation originated from phosphate. Using various techniques such as flow-cytometry to measure surface presented proteins, we confirmed that endogenous APP is essential for ferroportin persistence on the neuronal surface. Therefore, despite lacking ferroxidase activity, APP still supports iron export from neurons.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Protein Precursor / metabolism*
Animals
Cation Transport Proteins / metabolism*
Ceruloplasmin / metabolism*
HEK293 Cells
Humans
Mice
Oxidation-Reduction

Substances

Amyloid beta-Protein Precursor
Cation Transport Proteins
metal transporting protein 1
Ceruloplasmin

Grants and funding

The work carried out in Australia by BXW, LQL, PAA, AIB and JAD was supported by funding from the National Health & Medical Research Council (NHMRC) (Project grant #1025774 and #1044542). Work based in the United Kingdom by AT and JAD was funded by Alzheimer’s Research UK fellowship. The Florey Institute of Neuroscience and Mental Health acknowledges support from the Victorian Government for funding from the Operational Infrastructure Support Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.