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sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin
Author(s) -
McCarthy Ryan C,
Park YunHee,
Kosman Daniel J
Publication year - 2014
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201338064
Subject(s) - ferroportin , ferrous , efflux , chemistry , microbiology and biotechnology , transferrin receptor , dmt1 , hepcidin , biochemistry , transporter , iron homeostasis , biology , metabolism , transferrin , gene , immunology , inflammation , organic chemistry
A sequence within the E 2 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 sAPP α 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.