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.
Highlights
Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where Amyloid precursor protein (APP) is overexpressed, and a potential role of sAPPα or other nonamyloid APP fragments as acute modulators of mitochondrial metabolism
Cell proliferation was measured in control, APP wild-type and APP mutant cells over 72 h using the trypan blue exclusion assay (Fig. 1c), and confirmed that overexpression of either form of APP does not lead to decreased proliferation or cell death within these experimental parameters
Our results indicate that increased APP wild-type levels lead to a down-regulation of oxidative phosphorylation (OXPHOS), and enhanced glycolytic metabolism
Summary
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 nonamyloid APP fragments as acute modulators of mitochondrial metabolism. The non-amyloidogenic pathway involves cleavage of APP by α-secretase, producing a large N-terminal ectodomain, sAPPα, which is secreted into the extracellular medium[6], and an 83 amino-acid C-terminal fragment, which is subsequently cleaved by γ-secretase, producing a short peptide called p37. The amyloidogenic pathway involves cleavage by β-secretase, resulting in the release of soluble APP β (sAPPβ) into the extracellular medium, and a 99 amino acid C-terminal fragment in the membrane[17]. Subsequent cleavage of this fragment by γ-secretase generates the Aβ peptide. (d) Lactate production is significantly increased in cells that overexpress APP wild-type, relative to both control and APP mutant cells after 48 h in culture.
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