title: sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.
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.
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences University at Buffalo, Buffalo, NY, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: McCarthy
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences University at Buffalo, Buffalo, NY, USA.
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Park
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences University at Buffalo, Buffalo, NY, USA camkos@buffalo.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kosman
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D002570:Ceruloplasmin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D000098742:Ferroportin
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D027682:Cation Transport Proteins; D000098742:Ferroportin; D007501:Iron; D002570:Ceruloplasmin
keywords: blood‐brain barrier; brain iron metabolism; ferroportin; iron transport; sAPP