University of Leeds, United Kingdom
Title: Amyloid-β precursor protein presence on the neuron surface is required for the iron pore ferroportin to efflux iron.
Upon completing his Ph.Dat University of Wales College of Medicine, Cardiff in 2002, Jamesstudied in the US and Australia before recently returning to the UK. At present he concurrently runs research teams at the University of Leeds, UK and The Florey Institute of Neuroscience and Mental Health in Melbourne, Australia. In recognition of his strong involvement in identifying the iron regulatory role of β-Amyloid precursor protein (APP) through tau’s assistance in its transport to the neuron surface he was awarded the JBC/Herb Tabor Young International Investigator awarding 2012. Continued support is provided through an Alzheimer’s Research UK Senior Fellowship and projects funded by the ERC and Australian NHMRC.
Iron is an integral cofactor in many metabolic processes involved in transcriptional signaling, synapse formation and neuroplasticity, in all of which a function for amyloid- precursor protein (APP) has also been heavily implicated but remained unclear. Imbalances in intraneuronal iron are a predominant catalyst for the production of reactive oxygen species, particularly within iron accumulating neurodegenerative diseases such as Alzheimer’s disease. While APP has historically been associated with AD due to the prevalence of the APP derived amyloid-β (Aβ) peptide within insoluble extracellular ‘plaques’ deposited within the AD brain, we recently discovered that APP has a role in neuronal iron homeostasis by, in part, promoting iron efflux through cell surface stabilization of the iron pore ferroportin. Detailed cell surface characterization confirms that the location offerroportin on the neuron surface is increased upon iron incubation and is dependent upon APP. By altering the trafficking of APP to the cell surface via tau or the proteolyticprocessing of APP, consequential changes in neuronal iron homeostasis arise. Deletion of tau decreased cell surface APP expression, resulting in an age-dependent neuronal iron accumulation that parallels studies with APP depletion. Comparably, enhancing the amyloidogenicpathway of APP processing leads to intracellular iron accumulation.With increased amyloidogenic processing of APP and post-translational modification of tau being major contributors to sporadic AD, these studies increase our understanding as to why iron accumulation and increased susceptibility to reactive oxygen species neurotoxicity are prevalent with this disease.