Lopez 2017 Sci Rep

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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.

» PMID: 28852095

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 (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.


Bioblast editor: Kandolf G 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