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

ABSTRACT: Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPP?) 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 (A?) at the expense of sAPP? and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between A? and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or A? on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not A?, 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 A? toxicity, since higher levels of endogenous A? in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of ?-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 sAPP? or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism.

SUBMITTER: Lopez Sanchez MIG 

PROVIDER: S-EPMC5574989 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature