| First Author | Cimdins K | Year | 2019 |
| Journal | Mol Neurobiol | Volume | 56 |
| Issue | 8 | Pages | 5471-5482 |
| PubMed ID | 30612335 | Mgi Jnum | J:318549 |
| Mgi Id | MGI:6860104 | Doi | 10.1007/s12035-018-1460-7 |
| Citation | Cimdins K, et al. (2019) Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity. Mol Neurobiol 56(8):5471-5482 |
| abstractText | 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 alpha (sAPPalpha), 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 sAPPalpha 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 sAPPalpha 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 sAPPalpha 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. |
