Lopez 2017 Sci Rep
Lopez Sanchez MIG, Waugh HS, Tsatsanis A, Wong BX, Crowston JG, Duce JA, Trounce IA (2017) Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta. Sci Rep 7:9835. |
Lopez Sanchez MIG, Waugh HS, Tsatsanis A, Wong BX, Crowston JG, Duce JA, Trounce IA (2017) Sci Rep
Abstract: Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPΞ±) 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 (AΞ²) at the expense of sAPPΞ± and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between AΞ² and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or AΞ² on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not AΞ², 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 AΞ² toxicity, since higher levels of endogenous AΞ² in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of Ξ²-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 sAPPΞ± or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism.
β’ Bioblast editor: Kandolf G β’ O2k-Network Lab: AU Melbourne Trounce IA
Labels: MiParea: Respiration
Pathology: Alzheimer's, Cancer
Organism: Human
Preparation: Permeabilized cells Enzyme: Complex IV;cytochrome c oxidase
Coupling state: LEAK, OXPHOS, ET Pathway: N, NS, ROX HRR: Oxygraph-2k
Labels, 2017-12