Abstract
Ceruloplasmin is a ferroxidase that interacts with ferroportin to export cellular iron, but is not expressed in neurons. We recently reported that the amyloid precursor protein (APP) is the analogous iron-exporting chaperone for neurons and other cells. The ferroxidase activity of APP has since been called into question. Using a triplex Fe2+ oxidation assay, we analyzed the activity of a soluble form of APP (sAPPα) within a buffer of physiological pH and anionic charge, and determined that iron oxidation originated from phosphate. Using various techniques such as flow-cytometry to measure surface presented proteins, we confirmed that endogenous APP is essential for ferroportin persistence on the neuronal surface. Therefore, despite lacking ferroxidase activity, APP still supports iron export from neurons.
Highlights
Since its discovery, much of the research of the type 1 transmembrane protein bamyloid precursor protein (APP) has focused on its proteolytic components, the b-amyloid (Ab) peptide that accumulates in Alzheimer’s disease
We revisited the in vitro experiments testing sAPPa ferroxidase activity previously presented as part of our primary publication [2]
Having excluded ferroxidase activity as being of relevance to the mechanism by which APP facilitates the efflux of intracellular iron [2, 17], we investigated APP interaction with the iron exporter FPN
Summary
Much of the research of the type 1 transmembrane protein bamyloid precursor protein (APP) has focused on its proteolytic components, the b-amyloid (Ab) peptide that accumulates in Alzheimer’s disease. APP Mechanism in Neuronal Iron Export growing functional list by reporting that both the full-length membrane bound and the cleaved soluble extracellular form of sAPPa, but not other family members amyloid precursor-like protein (APLP) 1 and 2, facilitate the efflux of iron from APP-expressing cells such as neurons [2]. Unregulated hydroxyl radical (OHN) and ROS production is damaging to the cell [6] and have been associated with aging and disease, in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and aceruloplasminemia, where iron accumulates in affected tissue [7]
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