Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity

Mol Neurobiol. 2019 Aug;56(8):5471-5482. doi: 10.1007/s12035-018-1460-7. Epub 2019 Jan 5.


Mitochondrial complex I dysfunction is the most common respiratory chain defect in human disorders and a hotspot for neurodegenerative diseases. Amyloid precursor protein (APP) and its non-amyloidogenic processing products, in particular soluble APP α (sAPPα), have been shown to provide neuroprotection in models of neuronal injury; however, APP-mediated protection from acute mitochondrial injury has not been previously reported. Here, we use the plant-derived pesticide rotenone, a potent complex I-specific mitochondrial inhibitor, to discover neuroprotective effects of APP and sAPPα in vitro, in neuronal cell lines over-expressing APP, and in vivo, in a retinal neuronal rotenone toxicity mouse model. Our results show that APP over-expression is protective against rotenone toxicity in neurons via sAPPα through an autocrine/paracrine mechanism that involves the Pi3K/Akt pro-survival pathway. APP-/- mice exhibit greater susceptibility to retinal rotenone toxicity, while intravitreal delivery of sAPPα reduces inner retinal neuronal death in wild-type mice following rotenone challenge. We also show a significant decrease in human retinal expression of APP with age. These findings provide insights into the therapeutic potential of non-amyloidogenic processing of APP in complex I-related neurodegeneration.

Keywords: Amyloid precursor protein; Complex I; Mitochondria; Neuroprotection; Retina; Rotenone.

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology*
  • Neuroprotection / drug effects*
  • Neuroprotective Agents / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Rotenone / toxicity*
  • Toxicity Tests*
  • Young Adult


  • Amyloid beta-Protein Precursor
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Rotenone
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-akt