Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta

Identification: Lopez Sanchez, M. Isabel


Description

 

Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta
 
M. Isabel G. Lopez Sanchez 1, 2, Hayley S. Waugh 1, 2, Andrew Tsatsanis3, Bruce X. Wong3, 4, Jonathan G. Crowston 1, 2 James A. Duce 3, 4 and Ian A. Trounce 1, 2, *
1Centre for Eye Research Australia, 75 Commercial Road, Melbourne, 3004 Victoria, Australia;
2 Ophthalmology, University of Melbourne, Department of Surgery; 3School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT, United Kingdom; 4Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, 3052 Victoria, Australia
*Corresponding Author
      
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.
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 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 mitochondrial perturbations. Similarly, chemical inhibition of β-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. We also show that APP over-expression confers protection from the mitochondrial toxin rotenone in neuronal cell lines and sAPPα prevents cell death in an in vivo retinal model of rotenone toxicity.
Our results show the need for caution in attributing mitochondrial changes to Aβ when APP is overexpressed. Non-amyloidogenic processing of APP induces major changes in mitochondrial function that are not detrimental and can be protective of mitochondrial oxidative phosphorylation inhibition.

 

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