Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention
العنوان: | Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention |
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المؤلفون: | Scott Ayton, Adam P Gunn, James A. Duce, Ashley I. Bush, Andrew Tsatsanis, David Devos, Bruce X. Wong |
المصدر: | Molecular Psychiatry. 25:1958-1966 |
بيانات النشر: | Springer Science and Business Media LLC, 2020. |
سنة النشر: | 2020 |
مصطلحات موضوعية: | 0301 basic medicine, chemistry.chemical_classification, biology, Chemistry, Amyloid beta, Cell, Ferroportin, Peptide, Oxidative phosphorylation, Cleavage (embryo), Cell biology, Pathogenesis, 03 medical and health sciences, Cellular and Molecular Neuroscience, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, mental disorders, biology.protein, medicine, Efflux, Molecular Biology, 030217 neurology & neurosurgery |
الوصف: | 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. |
تدمد: | 1476-5578 1359-4184 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::1e316c74021ae8dae0da83a5d0e614dc https://doi.org/10.1038/s41380-020-0762-0 |
حقوق: | CLOSED |
رقم الأكسشن: | edsair.doi...........1e316c74021ae8dae0da83a5d0e614dc |
قاعدة البيانات: | OpenAIRE |
تدمد: | 14765578 13594184 |
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