GLT-1 Knockdown Inhibits Ceftriaxone-Mediated Improvements on Cognitive Deficits, and GLT-1 and xCT Expression and Activity in APP/PS1 AD Mice

JunXia Gao; LiZhe Liu; Chao Liu; ShuJuan Fan; LiRong Liu; ShuFeng Liu; Xiao-Hui Xian; Wen-Bin Li

doi:10.3389/fnagi.2020.580772

GLT-1 Knockdown Inhibits Ceftriaxone-Mediated Improvements on Cognitive Deficits, and GLT-1 and xCT Expression and Activity in APP/PS1 AD Mice

Front Aging Neurosci. 2020 Oct 6:12:580772. doi: 10.3389/fnagi.2020.580772. eCollection 2020.

Authors

JunXia Gao¹, LiZhe Liu¹, Chao Liu², ShuJuan Fan¹, LiRong Liu¹, ShuFeng Liu², Xiao-Hui Xian¹, Wen-Bin Li¹

Affiliations

¹ Department of Pathophysiology, Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China.
² Hebei Key Lab of Laboratory Animal Science, Laboratory Animal Center, Hebei Medical University, Shijiazhuang, China.

Abstract

Objective: Glutamate transporter-1 (GLT-1) and system x _c ^- mediate glutamate uptake and release, respectively. Ceftriaxone has been reported to upregulate GLT-1 expression and improve cognitive decline in APP/PS1 mice. The aim of the present study was to elucidate the role of GLT-1 in ceftriaxone-mediated improvement on cognitive deficits and associated changes in xCT (catalytic subunit of system x _c ^-) expression and activity using GLT-1 knockdown APP/PS1 mice.

Methods: GLT-1 knockdown (GLT-1^±) mice were generated in C57BL/6J mice using the CRISPR/Cas9 technique and crossed to APP/PS1 mice to generate GLT-1^±APP/PS1 mice. The cognition was evaluated by novel object recognition and Morris water maze tests. GLT-1 and xCT expression, GLT-1 uptake for glutamate, and glutathione levels of hippocampus were assayed using Western blot and immunohistochemistry, ³H-glutamate, and glutathione assay kit, respectively.

Results: In comparison with wild-type mice, APP/PS1 mice exhibited significant cognitive deficits, represented with poor performance in novel object recognition and Morris water maze tests, downregulated GLT-1 expression and glutamate uptake. Ceftriaxone treatment significantly improved the above impairments in APP/PS1 mice, but had negligible impact in GLT-1^±APP/PS1 mice. The xCT expression increased in APP/PS1 and GLT-1^±APP/PS1 mice. This upregulation might be a compensatory change against the accumulated glutamate resulting from GLT-1 impairment. Ceftriaxone treatment restored xCT expression in APP/PS1 mice, but not in GLT-1^±APP/PS1 mice. Glutathione levels decreased in APP/PS1 mice in comparison to the wild-type group. After ceftriaxone administration, the decline in glutathione level was restored in APP/PS1 mice, but not in GLT-1^±APP/PS1 mice.

Conclusion: Ceftriaxone improves cognitive impairment of APP/PS1 mice by upregulating GLT-1-mediated uptake of glutamate and co-regulation of GLT-1 and xCT in APP/PS1 mice.

Keywords: APP/PS1 mice; GLT-1; GLT-1 knockdown; ceftriaxone; glutamate uptake; glutathione level; xCT.