An adenoviral vector encoded with the GPx-1 gene attenuates memory impairments induced by β-amyloid (1-42) in GPx-1 KO mice via activation of M1 mAChR-mediated signalling

Eun-Joo,Shin ¹Sung Hoon,Lee ²Naveen,Sharma ¹Bao Trong,Nguyen ¹Yoon Hee,Chung ³Sang Won,Kang ⁴Seung-Yeol,Nah ⁵Yu Jeung,Lee ⁶Toshitaka,Nabeshima ⁷Ji Hoon,Jeong ⁸Hyoung-Chun,Kim¹

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作者信息

1. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University
2. Department of Pharmacology, College of Pharmacy, Chung-Ang University
3. Department of Anatomy, College of Medicine, Chung-Ang University
4. Department of Life Science, College of Natural science, Ewha Womans University
5. Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and
6. Clinical Pharmacy, College of Pharmacy, Kangwon National University
7. Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health
8. Department of Global Innovative Drugs, Graduate School of Chung-Ang University, College of Medicine
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Abstract

Abstract In the present study, we examined whether glutathione peroxidase-1 (GPx-1), a major H2O2 scavenger in the brain, affects memory deficits induced by Aβ (1-42) in mice. Treatment with 400?pmol/5?μl Aβ (1-42) (i.c.v.) resulted in a reduction of GPx-1 expression in wild-type (WT) mice. An Aβ (1-42)-induced reduction in acetylcholine (ACh) level was observed in the hippocampus. Treatment with Aβ (1-42) consistently resulted in reduced expression and activity of choline acetyltransferase (ChAT) and in an increase in expression and activity of acetylcholinesterase (AChE). Upon examining each of the muscarinic acetylcholine receptors (mAChRs) and nicotinic AChRs, we noted that Aβ (1-42) treatment selectively reduced the levels of M1 mAChR. In addition, Aβ (1-42) induced a significant reduction in phospho-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. The cholinergic impairments induced by Aβ (1-42) were more pronounced in GPx-1 knockout mice than in WT mice. Importantly, an adenoviral vector encoded with the GPx-1 gene (Ad-GPx-1) significantly rescued Aβ (1-42)-induced cholinergic impairments in GPx-1 knockout mice. In addition, M1 mAChR antagonist dicyclomine significantly counteracted Ad-GPx-1-mediated increases in p-CREB and BDNF expression, as well as memory-enhancing effects in GPx-1 knockout mice, thus indicating that M1 mAChR might be a critical mediator for the rescue effects of Ad-GPx-1. Combined, our results suggest that GPx-1 gene protected against Aβ (1-42)-induced memory impairments via activation of M1 mAChR-dependent CREB/BDNF signalling.

Key words

Aβ (1-42)-induced memory impairment/GPx-1 knockout mice/GPx-1 gene-encoded adenovirus vector/M1 mAChR/CREB/BDNF/Hippocampus

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出版年

2021

Free radical research

SCI

ISSN：1071-5762

被引量4

参考文献量89

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