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.

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

Grant support

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.