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- Title
Glutathione Peroxidase-1 Knockout Facilitates Memory Impairment Induced by β-Amyloid (1–42) in Mice via Inhibition of PKC βII-Mediated ERK Signaling; Application with Glutathione Peroxidase-1 Gene-Encoded Adenovirus Vector.
- Authors
Shin, Eun-Joo; Chung, Yoon Hee; Sharma, Naveen; Nguyen, Bao Trong; Lee, Sung Hoon; Kang, Sang Won; Nah, Seung-Yeol; Wie, Myung Bok; Nabeshima, Toshitaka; Jeong, Ji Hoon; Kim, Hyoung-Chun
- 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.
- Subjects
GLUTATHIONE peroxidase; SELENOPROTEINS; GLUTATHIONE; REACTIVE oxygen species; PROTEIN kinase C; KNOCKOUT mice; ADENOVIRUSES; MICE
- Publication
Neurochemical Research, 2020, Vol 45, Issue 12, p2991
- ISSN
0364-3190
- Publication type
Article
- DOI
10.1007/s11064-020-03147-3