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

• Published in: Frontiers in aging neuroscience Vol. 12; p. 580772
• Main Authors: Gao, JunXia, Liu, LiZhe, Liu, Chao, Fan, ShuJuan, Liu, LiRong, Liu, ShuFeng, Xian, Xiao-Hui, Li, Wen-Bin
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 06.10.2020; Frontiers Media S.A
• Subjects: Age; Antibiotics; Ceftriaxone; Cognitive ability; CRISPR; GLT-1; GLT-1 knockdown; glutamate uptake; Glutamic acid transporter; Glutathione; glutathione level; Immunohistochemistry; Laboratory animals; Memory; Mutation; Neuroscience; Pathogenesis; Pattern recognition; Presenilin 1; Rodents; xCT; China; ceftriaxone; APP/PS1 mice; glutathione level; glutamate uptake; xCT; GLT-1 knockdown; GLT-1
• ISSN: 1663-4365; 1663-4365
• DOI: 10.3389/fnagi.2020.580772

Glutamate transporter-1 (GLT-1) and system x 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 ) expression and activity using GLT-1 knockdown APP/PS1 mice. 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, H-glutamate, and glutathione assay kit, respectively. 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. 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.