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

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=12

YEAR=2020

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2020.580772

DOI=10.3389/fnagi.2020.580772

ISSN=1663-4365

ABSTRACT=<sec><title>Objective</title><p>Glutamate transporter-1 (GLT-1) and system x<sub><italic>c</italic></sub><sup>–</sup> 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<sub><italic>c</italic></sub><sup>–</sup>) expression and activity using GLT-1 knockdown APP/PS1 mice.</p></sec><sec><title>Methods</title><p>GLT-1 knockdown (GLT-1<sup>±</sup>) mice were generated in C57BL/6J mice using the CRISPR/Cas9 technique and crossed to APP/PS1 mice to generate GLT-1<sup>±</sup>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, <sup>3</sup>H-glutamate, and glutathione assay kit, respectively.</p></sec><sec><title>Results</title><p>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<sup>±</sup>APP/PS1 mice. The xCT expression increased in APP/PS1 and GLT-1<sup>±</sup>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<sup>±</sup>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<sup>±</sup>APP/PS1 mice.</p></sec><sec><title>Conclusion</title><p>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.</p></sec>