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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.

Author information

1
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
2
Ophthalmology, Department of Surgery, The University of Melbourne, 75 Commercial Road, Melbourne, Victoria, 3004, Australia.
3
Department of Oncology, University of Oxford, Oxford, UK.
4
Department of Medicine, St. Vincent's Hospital, The University of Melbourne, 75 Commercial Road, Melbourne, Victoria, 3004, Australia.
5
Centre for Clinical Neuroscience and Neurological Research, St. Vincent's Hospital, Melbourne, Victoria, Australia.
6
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
7
The ALBORADA Drug Discovery Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
8
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
9
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. i.trounce@unimelb.edu.au.
10
Ophthalmology, Department of Surgery, The University of Melbourne, 75 Commercial Road, Melbourne, Victoria, 3004, Australia. i.trounce@unimelb.edu.au.
11
Department of Medicine, St. Vincent's Hospital, The University of Melbourne, 75 Commercial Road, Melbourne, Victoria, 3004, Australia. i.trounce@unimelb.edu.au.

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.

KEYWORDS:

Amyloid precursor protein; Complex I; Mitochondria; Neuroprotection; Retina; Rotenone

PMID:
30612335
DOI:
10.1007/s12035-018-1460-7

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