Vol.:(0123456789) 1 3 Neurochemical Research https://doi.org/10.1007/s11064-020-03147-3 ORIGINAL PAPER 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 Eun‑Joo Shin 1  · Yoon Hee Chung 2  · Naveen Sharma 1,8  · Bao Trong Nguyen 1  · Sung Hoon Lee 3  · Sang Won Kang 4  · Seung‑Yeol Nah 5  · Myung Bok Wie 6  · Toshitaka Nabeshima 7  · Ji Hoon Jeong 8  · Hyoung‑Chun Kim 1 Received: 23 July 2020 / Revised: 16 September 2020 / Accepted: 7 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract A growing body evidence suggests that selenium (Se) defciency is associated with an increased risk of developing Alzhei- mer’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.) signifcantly 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) signifcantly increased GPx-1 mRNA and GPx activity in the hippocampus of GPx-1 knockout mice. Adv-GPx-1 exposure also signifcantly blocked the neurotoxic changes induced by Aβ (1–42) in GPx-1 knockout mice. Treatment with ERK inhibitor U0126 did not signifcantly 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 Eun-Joo Shin and Yoon Hee Chung are the frst two authors equally contributed to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11064-020-03147-3) contains supplementary material, which is available to authorized users. * Ji Hoon Jeong jhjeong3@cau.ac.kr * Hyoung-Chun Kim kimhc@kangwon.ac.kr 1 Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 24341, Republic of Korea 2 Department of Anatomy, College of Medicine, Chung‐Ang University, Seoul, Seoul 06974, Republic of Korea 3 Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea 4 Department of Life Science, College of Natural Science, Ewha Womans University, Seoul 03760, Republic of Korea 5 Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 05029, Republic of Korea 6 Department of Veterinary Toxicology, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea 7 Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan 8 Department of Global Innovative Drugs, Graduate School of Chung-Ang University, College of Medicine, Chung-Ang University, Seoul 06974, Republic of Korea