Mol Neurobiol. 2019 Jan 5. doi: 10.1007/s12035-018-1460-7. [Epub ahead of print]Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity.
Cimdins K1,2, Waugh HS1,2, Chrysostomou V1,2, Lopez Sanchez MIG1,2, Johannsen VA3, Cook MJ4,5, Crowston JG1,2, Hill AF6, Duce JA7,8, Bush AI8, Trounce IA9,10,11.Abstract
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.
