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Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010 Sep 17;142(6):857-67. PubMed.
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Jikei University School of Medicine
Comment by George Perry, Xiongwei Zhu, Akihiko Nunomura, Paula I. Moreira, Rudy J. Castellani, Mark A. Smith
Amyloid-β Protein Precursor at the Center of Iron and Redox Homeostasis: The Amyloid Reparative Cascade Hypothesis
It is an overused statement that the brain is poorly protected from oxidative stress. That statement is now put to rest by the elegant and meticulous work of Ashley Bush and colleagues (Duce et al., 2010). Bush has shown the amyloid-β protein precursor (AβPP) has ferroxidase activities comparable to ceruloplasmin or ferritin. Ferroxidase, by stabilizing Fe+3, is at the center of protecting cells from Fe+2/Fe+3 cycling, with consequent hydroxyl radical production. Additionally, ferroxidase activity is essential for iron transport and tissue response to injury. These findings explain why, in the face of increased oxidative damage and response, ceruloplasmin is not induced (Castellani et al., 1999). AβPP, therefore, represents a unique system, adapted to the brain, to cope with iron homeostasis. These results suggest that the iron deposits surrounding Aβ deposits are due to ferroxidase activity rather than iron binding (Dong et al., 2003). It is not surprising that AβPP is a critical marker of axonal injury (Cochran et al., 1991) and repair, as both ceruloplasmin and ferritin play similar roles. When seen together with the antioxidant role of Aβ through copper chelation (Hayashi et al., 2007), the reparative power of the amyloid pathway cannot be questioned (Rottkamp et al., 2001; Castellani et al., 2009).
References:
Castellani RJ, Lee HG, Siedlak SL, Nunomura A, Hayashi T, Nakamura M, Zhu X, Perry G, Smith MA. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis. 2009;18(2):447-52. PubMed.
Castellani RJ, Smith MA, Nunomura A, Harris PL, Perry G. Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin?. Free Radic Biol Med. 1999 Jun;26(11-12):1508-12. PubMed.
Cochran E, Bacci B, Chen Y, Patton A, Gambetti P, Autilio-Gambetti L. Amyloid precursor protein and ubiquitin immunoreactivity in dystrophic axons is not unique to Alzheimer's disease. Am J Pathol. 1991 Sep;139(3):485-9. PubMed.
Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA, Perry G, Carey PR. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry. 2003 Mar 18;42(10):2768-73. PubMed.
Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010 Sep 17;142(6):857-67. PubMed.
Hayashi T, Shishido N, Nakayama K, Nunomura A, Smith MA, Perry G, Nakamura M. Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-beta peptide. Free Radic Biol Med. 2007 Dec 1;43(11):1552-9. PubMed.
Rottkamp CA, Raina AK, Zhu X, Gaier E, Bush AI, Atwood CS, Chevion M, Perry G, Smith MA. Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med. 2001 Feb 15;30(4):447-50. PubMed.
View all comments by Akihiko NunomuraMassachusetts General Hospital/Harvard University
In September's issue of Cell, the report by Duce et al. (2010) describes the novel finding that the underlying biochemical function of the Alzheimer’s amyloid precursor protein (APP) incorporates a dual role in iron metabolism. First, APP displays ferroxidase activity, which detoxifies deleterious Fe2+ into the storage form of iron as Fe3+. Second, it shows that APP has a clear role in iron export, where APP is in association with the well-known iron export protein, ferroportin, also associated with hemachromatosis and iron-storage disease. Thus, APP helps ferroportin to export iron and detoxify neurons from potential iron-accelerated oxidative stress. This is the culmination of a highly productive collaboration between the Oxidation Biology Group led by Ashley Bush (University of Melbourne) and the Neurochemistry laboratory of myself, Jack Rogers (Psych-Neuroscience, Massachusetts General Hospital at Harvard).
It had long been suspected that APP expression and function is regulated by iron and iron metabolism. This paper finally pinpoints this function, attributable to a “tell-tale” iron binding REXXE site (at residues 401-417 in the E2 domain of APP-770), confirmed to be an iron oxidase site in the APP protein itself (see U.S. Patent WO/2002/034766; Rogers et al., 2002). Also, there is a uniquely configured iron-responsive element (IRE) RNA stem loop in the 5’ untranslated region of the APP transcript (Rogers et al., 2002). IRE stem loops on mRNAs can be viewed as a genetic tag linking the particular protein expressed to iron metabolism.
This key APP-ferroxidase paper is complemented by another contribution from my lab to J. Biol. Chem. (see Cho et al., 2010) that defines how iron metabolism controls APP expression.
References:
Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H, Leiter L, McPhee J, Sarang SS, Utsuki T, Greig NH, Lahiri DK, Tanzi RE, Bush AI, Giordano T, Gullans SR. An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem. 2002 Nov 22;277(47):45518-28. Epub 2002 Aug 26 PubMed.
Cho HH, Cahill CM, Vanderburg CR, Scherzer CR, Wang B, Huang X, Rogers JT. Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1. J Biol Chem. 2010 Oct 8;285(41):31217-32. PubMed.
The Scripps Research Institute, FL campus
In August 2012, we published a paper in PLoS ONE entitled "A Synthetic Peptide with the Putative Iron Binding Motif of Amyloid Precursor Protein (APP) Does Not Catalytically Oxidize Iron." In this paper, we critically studied the ferroxidase activity of the FD1 peptide that was used by Duce et al. as part of their proof for ferroxidase activity in APP. Unlike Duce et al., we found that this peptide does not have ferroxidase activity. Moreover, we found several seminal inconsistencies in the data. We suggest that the ferroxidase activity of the APP should be re-evaluated.
References:
Ebrahimi KH, Hagedoorn PL, Hagen WR. A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP) does not catalytically oxidize iron. PLoS One. 2012;7(8):e40287. PubMed.
The Scripps Research Institute, FL campus
Following our initial study (Ebrahimi et al., 2012) we have published a new paper entitled "The Amyloid Precursor Protein (APP) Does Not Have a Ferroxidase Site in Its E2 Domain" (Honarmand Ebrahimi et al. 2013). In this work we critically studied the previously proposed ferroxidase activity of the E2 domain of APP (Duce et al. 2010). Our data show that E2 domain of APP does not have ferroxidase activity and reveal several inconsistencies in Duce et al.'s prior report.
The idea that the E2 domain of APP is involved in iron-export as a ferroxidase is possibly not valid.
References:
Ebrahimi KH, Hagedoorn PL, Hagen WR. A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP) does not catalytically oxidize iron. PLoS One. 2012;7(8):e40287. PubMed.
Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010 Sep 17;142(6):857-67. PubMed.
Honarmand Ebrahimi K, Dienemann C, Hoefgen S, Than ME, Hagedoorn PL, Hagen WR. The Amyloid Precursor Protein (APP) Does Not Have a Ferroxidase Site in Its E2 Domain. PLoS One. 2013;8(8):e72177. PubMed.
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