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Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention

Abstract

The proteolytic cleavage of β-amyloid precursor protein (APP) to form the amyloid beta (Aβ) peptide is related to the pathogenesis of Alzheimer’s disease (AD) because APP mutations that influence this processing either induce familial AD or mitigate the risk of AD. Yet Aβ formation itself may not be pathogenic. APP promotes neuronal iron efflux by stabilizing the cell-surface presentation of ferroportin, the only iron export channel of cells. Mislocalization of APP can promote iron retention, thus we hypothesized that changes in endocytotic trafficking associated with altered APP processing could contribute to the neuronal iron elevation and oxidative burden that feature in AD pathology. Here, we demonstrate, using genetic and pharmacological approaches, that endocytotic amyloidogenic processing of APP impairs iron export by destabilizing ferroportin on the cell surface. Conversely, preferential non-amyloidogenic processing of APP at the cell surface promotes ferroportin stabilization to decrease intraneuronal iron. A new Aβ-independent hypothesis emerges where the amyloidogenic processing of APP, combined with age-dependent iron elevation in the tissue, increases pro-oxidant iron burden in AD.

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Fig. 1: Iron increases retention of APP on the neuronal cell surface.
Fig. 2: Altering proteolytic cleavage of APP causes a response to intraneuronal iron levels and ferroportin location.
Fig. 3: Familial mutations in APP that alter proteolytic processing affect intraneuronal iron by altering ferroportin location.
Fig. 4: The endocytotic pathway required for amyloidogenic processing of APP affects intraneuronal iron and ferroportin location.
Fig. 5: The influence of proteolytic processing of APP on iron efflux through ferroportin (FPN).

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Acknowledgements

We are grateful to Prof. Colin Masters for providing access to the 22C11 antibody and Prof. Nigel Hooper for the fluorescence peptide based on the APPSwe sequence (FAM-ISEVNLDAEFR-TAMRA) that was originally gifted to him by GlaxoSmithKline, Stevenage, UK. Flow cytometry was performed by equipment and assistance from the Core Bioimaging facility at Faculty of Biological Sciences, Leeds. Work carried out was supported by Alzheimer’s Research UK, the European Research Council and Australian National Health & Medical Research Council (NHMRC) (#1061587).

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JAD designed the research with guidance from DD and AIB. BXW and AT performed all cell-based experiments with further neuronal culture evaluation carried out by APG. JAD analyzed the data and wrote the paper with BXW, APG, SA, DD, and AIB participating in the editing of the paper.

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Correspondence to James A. Duce.

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AIB is a shareholder in Prana Biotechnology Ltd, Cogstate Ltd, Brighton Biotech LLC, Grunbiotics Pty Ltd, Eucalyptus Pty Ltd, and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd.

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Tsatsanis, A., Wong, B.X., Gunn, A.P. et al. Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention. Mol Psychiatry 25, 1958–1966 (2020). https://doi.org/10.1038/s41380-020-0762-0

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