Journal
CNS NEUROSCIENCE & THERAPEUTICS
Volume 26, Issue 2, Pages 167-176Publisher
WILEY
DOI: 10.1111/cns.13212
Keywords
AMPK; autophagy; corticosterone; mTOR; neurotoxicity
Categories
Funding
- Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province, China
- Undergraduate Training Program for Innovation and Entrepreneurship Project of Hunan Province [2018XJXZ151]
- National Natural Science Foundation of China [81500349]
- Natural Science Foundation of Hunan Province, China [08JJ3036, 2016JJ2112]
- Health and Family Planning Commission of Hunan Province, China [B2017048]
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Aims Our previous study indicated that chronic stress caused autophagy impairment and subsequent neuron apoptosis in hippocampus. However, the mechanism underlying the stress-induced damage to neurons is unclear. In present work, we investigated whether stress-level glucocorticoids (GCs) GCs promoted PC12 cell damage via AMPK/mTOR signaling-mediated autophagy. Methods Chronic stress-induced PC12 cell injury model was built by treatment with high level corticosterone (CORT). Cell injury was evaluated by flow cytometry assay and transmission electron microscopy observation. Results Autophagy flux was measured based on the changes in LC3-II and P62 protein expressions, and the color alteration of mCherry-GFP-LC3-II transfection. Our results showed that CORT not only increased cell injury and apoptosis, but also dysregulated AMPK/mTOR signaling-mediated autophagy flux, as indicated by the upregulated expression of LC3-II and P62 proteins, and the lowered ration of autolysosomes to autophagosomes. Mechanistically, our results demonstrated that autophagy activation by AMPK activator metformin or mTOR inhibitor rapamycin obviously promotes cell survival and autophagy flux, improved mitochondrial ultrastructure, and reduced expression of Cyt-C and caspase-3 in CORT-induced PC12 cells. Conclusion These results indicate that high CORT triggers PC12 cell damage through disrupting AMPK/mTOR-mediated autophagy flux. Targeting this signaling may be a promising approach to protect against high CORT and chronic stress-induced neuronal impairment.
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