Unknown

Dataset Information

0

Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity.


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 ? (sAPP?), 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 sAPP? 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 sAPP? 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 sAPP? 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.

SUBMITTER: Cimdins K 

PROVIDER: S-EPMC6614131 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications


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  ...[more]

Similar Datasets

| S-EPMC7723294 | biostudies-literature
| S-EPMC2191956 | biostudies-other
| S-EPMC1808499 | biostudies-literature
| S-EPMC4987443 | biostudies-literature
| S-EPMC3628100 | biostudies-literature
| S-EPMC24195 | biostudies-literature
| S-EPMC3534898 | biostudies-literature
| S-EPMC4991393 | biostudies-literature
| S-EPMC1224625 | biostudies-literature
| S-EPMC2685684 | biostudies-literature