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<p>Celastrol is a promising therapeutic candidate for neurodegenerative diseases. However, the underlying mechanism of celastrol on Alzheimer’s disease (AD) remains poorly understood. This study aims to investigate the potential effect of celastrol on treating AD using multi-omics. The AD rat model was established using D-galactose combined with Aβ<sub>25-35</sub> and subsequently treated with celastrol at doses of 0.7&#xa0;mg/kg and 2.8&#xa0;mg/kg respectively. Cognitive and memory impairments were assessed using the Morris water maze test. Neuronal damage in the hippocampal region was evaluated through Nissl staining. The expression levels of Iba1, Aβ<sub>1-42</sub>, and p-tau were determined using immunohistochemical staining, ELISA, and western-blotting. Transcriptomic and metabolomic analyses were performed to profile RNA and metabolite expression. The composition and diversity of gut microbiota were analyzed via 16S rRNA gene sequencing. Spearman correlation analysis was employed to integrate transcriptomic-metabolomic and 16S rRNA-metabolomic data. Compared with the AD group, a intervention of 2.8&#xa0;mg/kg celastrol could significantly reduce the escape latency (<i>p</i> &lt; 0.05), increase the frequency of crossing the target platform and duration in the target quadrant (<i>p</i> &lt; 0.05). In addition, celastrol could significantly inhibited the expression levels of Iba1, TNF-α, and IL-1β (<i>p</i> &lt; 0.05), reduce the number of damaged neurons (<i>p</i> &lt; 0.05), and decrease the expression levels of p-tau and Aβ<sub>1-42</sub> (<i>p</i> &lt; 0.05). Furthermore, a total of 309 differentially expressed genes (DEGs) and 96 differentially expressed metabolites (DEMs) were detected between the celastrol and AD groups. Among the DEMs, phospholipids including 16:0–22:6 PE and 18:0–22:6 PC were significantly regulated by celastrol. 16S rRNA analysis indicated that celastrol could increase the <i>Firmicutes/Bacteroidota</i> ratio, as well as enhance the abundances of <i>g_Romboutsia</i> and <i>g_Clostridium_sensu_stricto_1.</i> Combined transcriptomic-metabolomic analysis indicated that the expressions of 16:0–22:6 PE and 18:0–22:6 PC might be regulated by multiple genes including LOC103689940, Impad1, and Sult1c2a. And combined 16S rRNA-metabolomic analysis indicated that 16:0–22:6 PE and 18:0–22:6 PC metabolism might be significantly correlated with <i>g_Romboutsia, g_Clostridium_sensu_stricto_1</i>, and <i>g_Turicibacter.</i> In conclusion, celastrol could improve cognitive and memory dysfunction in AD rats. The regulation of phospholipids or sphingolipid metabolism and gene expression in metabolic pathway might be linked with alteration in intestinal microbiota.</p>

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Integrating transcriptome, metabolome and 16S rRNA sequencing to reveal the effect of celastrol on Alzheimer’s disease in rats

  • 期刊论文

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  • 发表日期：

    2026年7月20日

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  • Yan Wang,
  • Lan Liu,
  • Yongcang Zhang,
  • Ping Luo,
  • Qin Xiang,
  • Liang Tang

摘要

Celastrol is a promising therapeutic candidate for neurodegenerative diseases. However, the underlying mechanism of celastrol on Alzheimer’s disease (AD) remains poorly understood. This study aims to investigate the potential effect of celastrol on treating AD using multi-omics. The AD rat model was established using D-galactose combined with Aβ25-35 and subsequently treated with celastrol at doses of 0.7 mg/kg and 2.8 mg/kg respectively. Cognitive and memory impairments were assessed using the Morris water maze test. Neuronal damage in the hippocampal region was evaluated through Nissl staining. The expression levels of Iba1, Aβ1-42, and p-tau were determined using immunohistochemical staining, ELISA, and western-blotting. Transcriptomic and metabolomic analyses were performed to profile RNA and metabolite expression. The composition and diversity of gut microbiota were analyzed via 16S rRNA gene sequencing. Spearman correlation analysis was employed to integrate transcriptomic-metabolomic and 16S rRNA-metabolomic data. Compared with the AD group, a intervention of 2.8 mg/kg celastrol could significantly reduce the escape latency (p < 0.05), increase the frequency of crossing the target platform and duration in the target quadrant (p < 0.05). In addition, celastrol could significantly inhibited the expression levels of Iba1, TNF-α, and IL-1β (p < 0.05), reduce the number of damaged neurons (p < 0.05), and decrease the expression levels of p-tau and Aβ1-42 (p < 0.05). Furthermore, a total of 309 differentially expressed genes (DEGs) and 96 differentially expressed metabolites (DEMs) were detected between the celastrol and AD groups. Among the DEMs, phospholipids including 16:0–22:6 PE and 18:0–22:6 PC were significantly regulated by celastrol. 16S rRNA analysis indicated that celastrol could increase the Firmicutes/Bacteroidota ratio, as well as enhance the abundances of g_Romboutsia and g_Clostridium_sensu_stricto_1. Combined transcriptomic-metabolomic analysis indicated that the expressions of 16:0–22:6 PE and 18:0–22:6 PC might be regulated by multiple genes including LOC103689940, Impad1, and Sult1c2a. And combined 16S rRNA-metabolomic analysis indicated that 16:0–22:6 PE and 18:0–22:6 PC metabolism might be significantly correlated with g_Romboutsia, g_Clostridium_sensu_stricto_1, and g_Turicibacter. In conclusion, celastrol could improve cognitive and memory dysfunction in AD rats. The regulation of phospholipids or sphingolipid metabolism and gene expression in metabolic pathway might be linked with alteration in intestinal microbiota.