ArticlePloS one2013
The amyloid precursor protein (APP) does not have a ferroxidase site in its E2 domain.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 27 citations in OpenAlex.
- How does iron cross the abluminal membrane of the blood-brain barrier.Experimental & molecular medicine · 2026Review
- Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases.MedComm · 2026Review
- Lactoferrin: from the structure to the functional orchestration of iron homeostasis.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2023Review
- Parkinson's Disease Dementia: Synergistic Effects of Alpha-Synuclein, Tau, Beta-Amyloid, and Iron.Frontiers in aging neuroscience · 2021Article
- Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer's disease from a ferroptosis perspective.Progress in neurobiology · 2020Review
- Is brain iron trafficking part of the physiology of the amyloid precursor protein?Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2019Article
- The Ferroxidase Hephaestin But Not Amyloid Precursor Protein is Required for Ferroportin-Supported Iron Efflux in Primary Hippocampal Neurons.Cellular and molecular neurobiology · 2018Article
- The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease.Frontiers in neuroscience · 2017Review
- Iron transport across the blood-brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy.Cellular and molecular life sciences : CMLS · 2015Review
- The role of iron in brain ageing and neurodegenerative disorders.The Lancet. Neurology · 2014Review
- sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.EMBO reports · 2014Article
- Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis.Biochemical pharmacology · 2014Review
- Glial cell ceruloplasmin and hepcidin differentially regulate iron efflux from brain microvascular endothelial cells.PloS one · 2014Article
- Article
- The iron regulatory capability of the major protein participants in prevalent neurodegenerative disorders.Frontiers in pharmacology · 2014Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ubiquitous 24-meric iron-storage protein ferritin and multicopper oxidases such as ceruloplasmin or hephaestin catalyze oxidation of Fe(II) to Fe(III), using molecular oxygen as oxidant. The ferroxidase activity of these proteins is essential for cellular iron homeostasis. It has been reported that the amyloid precursor protein (APP) also has ferroxidase activity. The activity is assigned to a ferroxidase site in the E2 domain of APP. A synthetic 22-residue peptide that carries the putative ferroxidase site of E2 domain (FD1 peptide) has been claimed to encompass the same activity. We previously tested the ferroxidase activity of the synthetic FD1 peptide but we did not observe any activity above the background oxidation of Fe(II) by molecular oxygen. Here we used isothermal titration calorimetry to study Zn(II) and Fe(II) binding to the natural E2 domain of APP, and we employed the transferrin assay and oxygen consumption measurements to test the ferroxidase activity of the E2 domain. We found that this domain neither in the presence nor in the absence of the E1 domain binds Fe(II) and it is not able to catalyze the oxidation of Fe(II). Binding of Cu(II) to the E2 domain did not induce ferroxidase activity contrary to the presence of redox active Cu(II) centers in ceruloplasmin or hephaestin. Thus, we conclude that E2 or E1 domains of APP do not have ferroxidase activity and that the potential involvement of APP as a ferroxidase in the pathology of Alzheimer's disease must be re-evaluated.
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