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Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention
- Source :
- Molecular Psychiatry. 25:1958-1966
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 14765578 and 13594184
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Molecular Psychiatry
- Accession number :
- edsair.doi...........1e316c74021ae8dae0da83a5d0e614dc