Abstract
ObjectiveGlutamate transporter-1 (GLT-1) and system xc– 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 xc–) expression and activity using GLT-1 knockdown APP/PS1 mice.MethodsGLT-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.ResultsIn 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.ConclusionCeftriaxone 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.
Highlights
Alzheimer’s disease (AD) is a common age-related neurodegenerative disease with learning and memory impairment, and progressive dementia (Selkoe, 2002)
Ceftriaxone treatment significantly improved the above impairments in APP/PS1 mice, but had negligible impact in glutamate transporter-1 (GLT-1)±APP/PS1 mice
The decline in glutathione level was restored in APP/PS1 mice, but not in GLT-1 knockdown (GLT-1±)APP/PS1 mice
Summary
Alzheimer’s disease (AD) is a common age-related neurodegenerative disease with learning and memory impairment, and progressive dementia (Selkoe, 2002). The primary neurotransmitter of glutamatergic neuronal system, exerts an essential function in learning and memory (Willard and Koochekpour, 2013). The concentration of glutamate in the synaptic cleft is principally regulated by glutamate transporters, especially glutamate transporter-1 (GLT-1), which accounts for a major role in glutamate uptake and exerts an important role in reutilization of glutamate as a neurotransmitter and prevention of glutamate excitotoxicity (Haugeto et al, 1996; Rothstein et al, 1996). Glutamate uptake activity in astrocytes derived from the cortex of patients with AD is significantly reduced (Liang et al, 2002; Scott et al, 2011). The reports suggest that regulation of GLT-1 expression and uptake activity may be protective against cognitive deficits in AD
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