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Open Access

sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin

Ryan C McCarthy, Yun‐Hee Park, Daniel J Kosman

Author Affiliations

  1. Ryan C McCarthy1,
  2. Yun‐Hee Park1 and
  3. Daniel J Kosman*,1
  1. 1Department of Biochemistry, School of Medicine and Biomedical Sciences University at Buffalo, Buffalo, NY, USA
  1. *Corresponding author. Tel: +1 716 829 2842; Fax: +1 716 829 2661; E‐mail: camkos{at}buffalo.edu

Abstract

A sequence within the E2 domain of soluble amyloid precursor protein (sAPP) stimulates iron efflux. This activity has been attributed to a ferroxidase activity suggested for this motif. We demonstrate that the stimulation of efflux supported by this peptide and by sAPPα is due to their stabilization of the ferrous iron exporter, ferroportin (Fpn), in the plasma membrane of human brain microvascular endothelial cells (hBMVEC). The peptide does not bind ferric iron explaining why it does not and thermodynamically cannot promote ferrous iron autoxidation. This peptide specifically pulls Fpn down from the plasma membrane of hBMVEC; based on these results, FTP, for ferroportin‐targeting peptide, correctly identifies the function of this peptide. The data suggest that in stabilizing Fpn via the targeting due to the FTP sequence, sAPP will increase the flux of iron into the cerebral interstitium. This inference correlates with the observation of significant iron deposition in the amyloid plaques characteristic of Alzheimer's disease.

Synopsis

Embedded Image

sAPP binds to ferroportin in the basal membrane of human brain microvascular endothelial cells of the blood‐brain barrier. This stabilizes ferroportin in the membrane and stimulates iron efflux at the brain side of these cells.

  • Iron efflux into the brain is supported by ferroportin in the basal plasma membrane of brain microvascular endothelial cells of the blood‐brain barrier.

  • sAPP binds to ferroportin via a short peptide motif.

  • This stabilizes ferroportin in the membrane and supports a stimulated iron efflux into the brain.

  • Received October 3, 2013.
  • Revision received April 7, 2014.
  • Accepted April 30, 2014.

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