Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta
| العنوان: | Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta |
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| المؤلفون: | M Isabel G Lopez Sanchez, Bruce X. Wong, James A. Duce, Jonathan G Crowston, Andrew Tsatsanis, Hayley S Waugh, Ian A. Trounce |
| المصدر: | Scientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) Scientific Reports |
| بيانات النشر: | Nature Publishing Group, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Transcription, Genetic, Amyloid beta, Cell Respiration, Gene Dosage, lcsh:Medicine, Oxidative phosphorylation, Mitochondrion, Neuroprotection, Oxidative Phosphorylation, Article, Cell Line, Electron Transport Complex IV, Amyloid beta-Protein Precursor, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, mental disorders, medicine, Amyloid precursor protein, Humans, lcsh:Science, Neurons, Amyloid beta-Peptides, Multidisciplinary, biology, lcsh:R, Neurotoxicity, P3 peptide, medicine.disease, Mitochondria, Enzyme Activation, Genes, Mitochondrial, 030104 developmental biology, Biochemistry, Mutation, biology.protein, lcsh:Q, Amyloid Precursor Protein Secretases, Glycolysis, Amyloid precursor protein secretase, 030217 neurology & neurosurgery |
| الوصف: | Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer’s disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aβ) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aβ and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Aβ on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Aβ, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Aβ toxicity, since higher levels of endogenous Aβ in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of β-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPα or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8bf666421fcee2a4526b49a30ca0a30f https://eprints.whiterose.ac.uk/121486/1/duce.pdf |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8bf666421fcee2a4526b49a30ca0a30f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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