Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity.
Mol Neurobiol
; 56(8): 5471-5482, 2019 Aug.
Article
in En
| MEDLINE
| ID: mdl-30612335
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Rotenone
/
Amyloid beta-Protein Precursor
/
Toxicity Tests
/
Neuroprotection
/
Neurons
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Adult
/
Aged
/
Aged80
/
Animals
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Language:
En
Journal:
Mol Neurobiol
Journal subject:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Year:
2019
Type:
Article
Affiliation country:
Australia