Abstract
Abstract: A growing body evidence suggests that selenium (Se) deficiency is associated with an increased risk of developing Alzheimer’s disease (AD). Se-dependent glutathione peroxidase-1 (GPx-1) of a major antioxidant enzyme, and the most abundant isoform of GPx in the brain. In the present study, we investigated whether GPx-1 is protective against memory impairments induced by beta-amyloid (Aβ) (1–42) in mice. As the alteration of protein kinase C (PKC)-mediated ERK activation was recognized in the early stage of AD, we examined whether the GPx-1 gene modulates Aβ (1–42)-induced changes in PKC and ERK levels. We observed that Aβ (1–42) treatment (400 pmol, i.c.v.) significantly decreased PKC βII expression in the hippocampus of mice. Aβ (1–42)-induced neurotoxic changes [i.e., oxidative stress (i.e., reactive oxygen species, 4-hydroxy-2-noneal, and protein carbonyl), reduced PKC βII and phospho-ERK expressions, and memory impairment under Y-maze and passive avoidance test] were more pronounced in GPx-1 knockout than in wild type mice. Importantly, exposure to a GPx-1 gene-encoded adenovirus vector (Adv-GPx-1) significantly increased GPx-1 mRNA and GPx activity in the hippocampus of GPx-1 knockout mice. Adv-GPx-1 exposure also significantly blocked the neurotoxic changes induced by Aβ (1–42) in GPx-1 knockout mice. Treatment with ERK inhibitor U0126 did not significantly change Adv-GPx-1-mediated attenuation in PKC βII expression. In contrast, treatment with PKC inhibitor chelerythrine (CHE) reversed Adv-GPx-1-mediated attenuation in ERK phosphorylation, suggesting that PKC βII-mediated ERK signaling is important for Adv-GPx-1-mediated potentials against Aβ (1–42) insult. Our results suggest that treatment with the antioxidant gene GPx-1 rescues Aβ (1–42)-induced memory impairment via activating PKC βII-mediated ERK signaling. Graphic Abstract: [Figure not available: see fulltext.].
Original language | English |
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Pages (from-to) | 2991-3002 |
Number of pages | 12 |
Journal | Neurochemical Research |
Volume | 45 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2020 |
Bibliographical note
Funding Information:This study was supported by 2018 Research Grant (PoINT) from Kangwon National University, and Kuhnil Pharmaceutical Co., Ltd., Republic of Korea. Naveen Sharma and Bao Trong Nguyen were supported by the BK21 PLUS program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education of Korea. The funders had no role in study design, data collection, data analysis, data interpretation, manuscript preparation, or decision to publish. Acknowledgements
Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.
Keywords
- Aβ (1–42)-induced memory impairment
- GPx-1 gene-encoded adenoviral vector
- GPx-1 knockout mice
- Hippocampus
- Oxidative stress
- PKC βII-mediated ERK phosphorylation