D-serine Ameliorates Motor and Cognitive Impairments in β-amyloid 1-42 Injected Mice by Inhibiting JNK Signaling Pathway

Hongqing Liu; Shiqi Li; Cuizhu Yang; Hui Jia; Ziting Gu; Xing Tu; Sumin Tian; Jing Liu; Guoying Li; Yuxin Ma

doi:10.1016/j.jchemneu.2020.101852

D-serine Ameliorates Motor and Cognitive Impairments in β-amyloid 1-42 Injected Mice by Inhibiting JNK Signaling Pathway

J Chem Neuroanat. 2020 Nov:109:101852. doi: 10.1016/j.jchemneu.2020.101852. Epub 2020 Aug 8.

Authors

Hongqing Liu¹, Shiqi Li¹, Cuizhu Yang¹, Hui Jia¹, Ziting Gu¹, Xing Tu¹, Sumin Tian², Jing Liu¹, Guoying Li¹, Yuxin Ma³

Affiliations

¹ Department of Anatomy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.
² Department of Physiology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.
³ Department of Anatomy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, China. Electronic address: mayuxin@gdpu.edu.cn.

PMID: 32781134
DOI: 10.1016/j.jchemneu.2020.101852

Abstract

The senile plaque formed by β-amyloid (Aβ) deposition in the brain is one of the main pathological features of Alzheimer's disease (AD), and the c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in the pathogenesis of AD. This study aimed to investigate that D-serine may ameliorate motor and cognitive impairment in Aβ injected mice by inhibiting JNK signaling pathway. Firstly, Kunming mice were injected intrahippocampally with Aβ_1-42 to build AD model. The mice were injected intraperitoneally with saline, D-serine, D-amino acid oxidase (DAAO), and Sodium benzoate (BE) for 10 consecutive days, respectively. Subsequently, the motor and cognitive functions of mice were detected by behavioral tests. The silver staining and immunohistochemical methods were used to detect the distributions of Aβ in the hippocampus of mice. ¹⁸F-2-Fluro-D-deoxy-glucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) scans were performed to detected glucose metabolism of Aβ_1-42 induced lesions. The expressions of relative JNK factors were detected by immunohistochemistry and Western blot methods. These results showed that Aβ severely impaired the motor and memory abilities of mice. The expressions of glial fibrillary acidic protein (GFAP), tumor necrosis factor (TNF-α), N-methyl-D-aspartate receptor 1 (NMDAR1), phospho-JNK (p-JNK), p-c-Jun and activating transcription factor 2 (ATF2) increased significantly. After D-serine treatment, the abilities of movement and memory of mice were improved, and the clearance rate of Aβ was accelerated. The expressions of GFAP, TNF-α, NMDAR1, p-JNK, p-c-Jun and ATF2 decreased significantly. DAAO and BE were administered to further validate these results. Therefore, this study showed that D-serine could alleviate the cognitive impairment of Aβ_1-42 injected mice by inhibiting JNK signaling pathway. These results provide more evidences for the effect of D-serine on AD and relevant mechanism to treat AD.

Keywords: D-serine; JNK; cognition; motor; β-amyloid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / pharmacology
Animals
Cognition / drug effects*
Cognitive Dysfunction / drug therapy*
Cognitive Dysfunction / metabolism
Disease Models, Animal
Hippocampus / drug effects*
Hippocampus / metabolism
MAP Kinase Signaling System / drug effects*
Male
Mice
Motor Activity / drug effects*
Serine / pharmacology
Serine / therapeutic use*

Substances

Amyloid beta-Peptides
Serine