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APPealing for a role in cellular iron efflux

  • Debomoy K. Lahiri
    Correspondence
    To whom correspondence should be addressed: Dept. of Psychiatry, Neuroscience Research Center, Indiana University School of Medicine, 320 W. 15th St., Indianapolis, IN 46202. Tel.: 317-274-2706
    Affiliations
    Department of Psychiatry and of Medical and Molecular Genetics, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202
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  • Bryan Maloney
    Affiliations
    Department of Psychiatry and of Medical and Molecular Genetics, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202
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  • Ruizhi Wang
    Affiliations
    Department of Psychiatry and of Medical and Molecular Genetics, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202
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Open AccessPublished:June 14, 2019DOI:https://doi.org/10.1074/jbc.L119.009216
      Dlouhy et al. (
      • Dlouhy A.C.
      • Bailey D.K.
      • Steimle B.L.
      • Parker H.V.
      • Kosman D.J.
      Fluorescence resonance energy transfer links membrane ferroportin, hephaestin but not ferroportin, amyloid precursor protein complex with iron efflux.
      ) recently refined how β-amyloid precursor protein (APP)
      The abbreviations used are: APP
      β-amyloid precursor protein
      sAPP
      secreted APP
      IRE
      iron response element
      AD
      Alzheimer's disease.
      2The abbreviations used are: APP
      β-amyloid precursor protein
      sAPP
      secreted APP
      IRE
      iron response element
      AD
      Alzheimer's disease.
      participates in iron (Fe) efflux and hinted that APP may be unnecessary for ferroportin-supported Fe efflux. APP and Fe efflux have long been our interest, given recent work on the APP mRNA 5′-UTR and how regulation of APP translation operates through an interleukin-1 acute box, an iron response element (IRE), where iron-responsive protein 1 (IRP1) binds, and a target sequence for microRNA-346 (
      • Long J.M.
      • Maloney B.
      • Rogers J.T.
      • Lahiri D.K.
      Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: implications in Alzheimer’s disease.
      ). Untangling the roles of IRE, IRP1, interleukin-1, and miR-346 at the APP 5′-UTR is critical in Alzheimer’s disease (AD). Fe regulation of APP levels through this site is well-documented (
      • Bandyopadhyay S.
      • Cahill C.
      • Balleidier A.
      • Huang C.
      • Lahiri D.K.
      • Huang X.
      • Rogers J.T.
      Novel 5′ untranslated region directed blockers of iron-regulatory protein-1 dependent amyloid precursor protein translation: implications for Down syndrome and Alzheimer’s disease.
      ). For example, that APP knockout alters Fe efflux in model mice (
      • Belaidi A.A.
      • Gunn A.P.
      • Wong B.X.
      • Ayton S.
      • Appukuttan A.T.
      • Roberts B.R.
      • Duce J.A.
      • Bush A.I.
      Marked age-related changes in brain iron homeostasis in amyloid protein precursor knockout Mice.
      ) argues in favor of APP regulation of Fe efflux. Dlouhy’s group (
      • Dlouhy A.C.
      • Bailey D.K.
      • Steimle B.L.
      • Parker H.V.
      • Kosman D.J.
      Fluorescence resonance energy transfer links membrane ferroportin, hephaestin but not ferroportin, amyloid precursor protein complex with iron efflux.
      ) reported that cellular APP plays no role in Fe homeostasis, at least with ferroportin, and secreted APP (sAPP) stabilizes ferroportin at the cell membrane (
      • McCarthy R.C.
      • Park Y.H.
      • Kosman D.J.
      sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.
      ). In normal cells, APP is processed by α- or β-secretase to generate sAPPα or sAPPβ, respectively. Post-translational secretase modification of APP alters neuronal Fe homeostasis (
      • Tsatsanis A.
      • Dickens S.
      • Kwok J.C.F.
      • Wong B.X.
      • Duce J.A.
      Post Translational Modulation of beta-Amyloid Precursor Protein Trafficking to the Cell Surface Alters Neuronal Iron Homeostasis.
      ). Because the APP they generated used a C-terminal tag that probably prevented secretase processing, it would have eliminated sAPP. They examined the specific form of APP that was not implicated in Fe metabolism in their own previous work (
      • McCarthy R.C.
      • Park Y.H.
      • Kosman D.J.
      sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.
      ) and suitably found further lack of implication. Nevertheless, their work of APP on Fe efflux will encourage researchers to examine effects of more AD relevance, such as the sAPPα (nonamyloidogenic pathway) versus sAPPβ (amyloidogenic pathway), and cytokines and microRNA regulation of APP in overall Fe metabolism as well as AD pathogenesis, progression, and therapeutics.

      References

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        Fluorescence resonance energy transfer links membrane ferroportin, hephaestin but not ferroportin, amyloid precursor protein complex with iron efflux.
        J. Biol. Chem. 2019; 294 (30647129): 4202-4214
        • Long J.M.
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        Novel 5′ untranslated region directed blockers of iron-regulatory protein-1 dependent amyloid precursor protein translation: implications for Down syndrome and Alzheimer’s disease.
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      Linked Article

      • Reply to Lahiri et al.: APPealing for a role in cellular iron efflux
        Journal of Biological ChemistryVol. 294Issue 24
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          Lahiri et al. (1) expressed concern that by not detecting FRET between ferroportin-CFP and APP-YFP,2 we “hinted that APP is unnecessary for ferroportin-supported Fe efflux.” There is no question that APP is unnecessary for ferroportin-dependent Fe efflux, as illustrated by the work by MacKenzie and co-workers (2), who, using expression of Fpn in Xenopus oocytes, have provided details of ferroportin function. Also, we have shown that whereas knockdown of the essential ferroxidase hephaestin reduces iron efflux in primary hippocampal neurons, knockdown of APP does not (3).
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