Transcriptomics and proteomics characterizing the antioxidant mechanisms of semaglutide in diabetic mice with cognitive impairment

Jan 31, 2025International journal of molecular medicine

Gene and protein changes linked to how semaglutide protects the brain from damage in diabetic mice with memory problems

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Abstract

Semaglutide treatment at 10 µg/kg resulted in 1,378 differentially expressed genes and 2,394 differentially expressed proteins in a diabetes-related cognitive decline model.

Semaglutide may enhance learning and memory functions while reducing damage in the hippocampus.
Comprehensive analysis revealed 40 common pathways linked to the antioxidant effects of semaglutide.
Activation of Acyl‑CoA oxidase 1 (ACOX1) during oxidative stress was suppressed by semaglutide.
The antioxidant and anti-apoptotic effects of semaglutide were partially reversed when ACOX1 was overexpressed.

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The aim of the present study was to investigate the neuroprotective effects of semaglutide in diabetes‑associated cognitive decline (DACD), while also exploring the underlying mechanisms targeting anti‑oxidative effects. The present study evaluated the antioxidant properties of semaglutide using a DACD model of inflammation. To investigate the underlying mechanisms, omics technologies were employed. Comprehensive transcriptomic and proteomic analysis of the cells was conducted to identify the pathways responsible for the observed antioxidant effects. Semaglutide demonstrated the potential to enhance learning and memory functions while mitigating hippocampal pathological damage. RNA‑sequencing and data‑independent acquisition proteomics analyses identified 13,511 differentially expressed genes and 588 differentially expressed proteins between the control and type 2 diabetes mellitus (T2DM) groups. In addition, 1,378 genes and 2,394 proteins exhibited a differential expression between the T2DM and semaglutide (10 µg/kg) treatment groups. A combined transcriptomic and proteomic analysis unveiled 40 common pathways. Acyl‑CoA oxidase 1 (ACOX1) was observed to be activated during oxidative stress and subsequently suppressed by semaglutide. Of note, the antioxidant and anti‑apoptotic properties of semaglutide in high glucose (HG) conditions were partially reversed upon ACOX1 overexpression. Overall, the present data provided molecular evidence to elucidate the physiological connections between semaglutide and neuronal function, and contribute to clarifying the role of semaglutide in combating oxidative stress and HG‑induced cognitive impairment.

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Transcriptomics and proteomics characterizing the antioxidant mechanisms of semaglutide in diabetic mice with cognitive impairment

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