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Regulation of iron homeostasis through beta-amyloid precursor processing in neuronal health and disease

Final Report Summary - APP & IRON TRANSPORT (Regulation of iron homeostasis through beta-amyloid precursor processing in neuronal health and disease.)

Work performed since the beginning of the project.
Disruption of iron homeostasis has historically led to neurodegeneration and accordingly impairment of APP to facilitate iron efflux implements iron induced excitotoxicity that is commonly observed in neurodegenerative disorders. Biological evidence of a role for APP in iron efflux via the iron pore protein ferroportin (FPN) has continued to be strengthened during the period of this award and a much clearer understanding into the physiological and pathological role of APP in iron homeostasis has been developed.
Using a newly developed triplex assay for in vitro oxidation studies, we have provided support that APP facilitates intraneuronal iron efflux by either using a physiologically abundant polyanion, or soluble Ceruloplasmin, present within the extraneuronal environment. During the research programme the iron transporter Lactoferrin was also identified as a binding partner to APP and led to a novel line of research that implicates APP and iron in a protective role with innate immunity. Recently, funds for the continuation of this research have been obtained and a scientific publication is in preparation.
Research developments during this award have also identified another route for APP-dependent regulation of neuronal iron that is highly relevant to Alzheimer’s disease (AD) pathology. Cleavage of APP is a known requisite for APP maintenance on the membrane surface. Currently submitted data now shows that altering the proteolytic processing of APP at the cell surface causes consequential changes in neuronal iron homeostasis. Enhancing the amyloidogenic pathway of APP processing, a major contributor to AD, leads to intracellular iron accumulation and these studies increase our understanding of iron accumulation in dementia.
Since our initial publication on tau’s regulatory role in iron efflux through APP transport, we have made further progress related to tau modulation and a role that lithium plays in modifying iron balance by tau. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, AD), and may explain lithium-associated motor symptoms in susceptible patients.
Support during this award on deferiprone (DFP) as a therapeutic strategy to restore iron homeostasis in mouse models with APP or tau depletion as well as related disease models strengthen its use in future clinical trials. Accordingly, Dr. James Duce has recently been invited onto the scientific advisory board of the current large phase III clinical trial with PD (FAIRPARK-II;
Potential impact of the outcomes.
The knowledge gained from this work will translate into fundamental outcomes in the science and/or practice of clinical medicine. Aspects of this research establish APP and tau as having a role in regulating iron within the brain, not only innovating the mechanism for iron efflux within general neurobiology but also providing an explanation for iron accumulation in neurodegenerative diseases with known problems with APP and tau. This in turn can provide a mechanism of action for some current therapeutics in neurodegenerative disease and aids future drug design to target iron-related damage.
Research career development and re-integration into the European research community.
The period of reintegration into the UK has increased my future potential as a highly competitive researcher and to be internationally recognized as a key leader in the discipline of neurobiology. During the period of this award I was offered a tenured lectureship position at the university that has enabled me to continue my research as well as support the development of students at the university. In addition, my inclusion into the iron research community in Europe is exemplified by my honorary position at Lille University and my scientific advisory board membership on the FAIRPARK-II clinical trial.