Transcriptional profile and quantitative proteomics revealed NGF-p75NTR-associated synaptic plasticity and heterogeneity for diabetic encephalopathy and the potential role of CoQ10 for diabetic induced cognitive deficits in mice

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-04-02 DOI:10.1016/j.bbadis.2025.167823

Qiong Xiang , Hu Lin , Li-Ni Liu , Jing Deng , Jia-Sheng Tao , Xian-Hui Li

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引用次数: 0

Abstract

Background

Diabetic encephalopathy (DE) is one of the diabetes complications, which showing heterogeneous at different stage in course of disease. CoQ10 is well-known for its neuroprotection effects in cardiovascular system. However, whether CoQ10 could modulate synaptic plasticity in DE remains unknown. This study aims to explore the cellular and molecular characteristics of CoQ10 and its potential role in diabetic induced cognitive deficits (DICD).

Methods

TMT-based quantitative proteomics was applied for investigating differentially expressed proteins (DEPs) among CoQ10 treated DICD, DICD and control (health) groups mice. Analysis of GO and KEGG pathway enrichment of DEPs among different groups. ScRNA-sequencing was applied for identifying heterogeneity among different groups; differentially expressed genes (DEGs), KEGG pathway enrichment were analyzed as well as Protein-protein interaction (PPI) networks were constructed. Western blotting was performed to validate the expressions of p75, BDNF in neurotrophin pathway and p-Akt in PI3K-Akt pathway, p-ERK as well as p-p38 in MAPK pathways among those groups.

Results

29 upregulated and 13 downregulated DEPs (db vs control, p < 0.05); 46 upregulated and 11 downregulated DEPs (db + CoQ10 vs control, p < 0.05) and 8 upregulated and 7 downregulated DEPs (db vs db + CoQ10,p < 0.05) were identified totally. 35 KEGG pathways were enriched by DEPs between DICD and CoQ10 treated DICD, including neurotrophing signaling pathway that had a crucial role in development, plasticity, and repair of the nervous system; Zfp369 that could interact with p75 and was upregulated after CoQ10 treatment among the down regulated DEPs in DICD; Further, scRNA-seq was applied, and the integrated analysis showed type IC spiral ganglion neuron with marker gene expression in cluster2,3,5 and 9, which were involved in synaptic plasticity regulation such as axon guidance, positive regulation of neuron projection development, negative regulation of BDNF binding and negative regulation basement membrane and dendritic microtuble formation as well as axoneme assembly.

Conclusions

CoQ10 treatment was very important in neural plasticity of DICD mice. It was the pioneering study to investigate DICD- related and CoQ10 treated proteomic changes and the correlated heterogeneity alterations between DICD and control. And also, NGF-p75NTR signaling pathways were significantly involved in synaptic plasticity regulation. The findings supplied the cellular and molecular evidence to clarify the potential role of CoQ10 in DICD, and combined drugs for diabetic patients in clinic.

Abstract Image

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转录谱和定量蛋白质组学揭示了糖尿病脑病中ngf - p75ntr相关的突触可塑性和异质性，以及CoQ10在糖尿病诱导的小鼠认知缺陷中的潜在作用。

背景：糖尿病性脑病（Diabetic enceopathy， DE）是糖尿病并发症之一，在病程的不同阶段表现出异质性。辅酶q10以其对心血管系统的神经保护作用而闻名。然而，辅酶q10是否能调节DE的突触可塑性尚不清楚。本研究旨在探讨辅酶q10的细胞和分子特征及其在糖尿病诱导的认知缺陷（DICD）中的潜在作用。方法：采用基于tmt的定量蛋白质组学方法研究CoQ10处理组、对照组和健康组小鼠的差异表达蛋白（DEPs）。不同组间DEPs的GO和KEGG通路富集分析。采用scrna测序技术鉴定各组间的异质性；分析差异表达基因（DEGs）、KEGG通路富集情况，构建蛋白-蛋白相互作用（PPI）网络。Western blotting检测各组神经营养因子通路中p75、BDNF、PI3K-Akt通路中p-Akt、MAPK通路中p-ERK、p-p38的表达。结果：29个dep上调，13个dep下调（与对照组相比，p ）。结论：CoQ10治疗对DICD小鼠的神经可塑性有重要影响。这是研究DICD相关和CoQ10治疗的蛋白质组学变化以及DICD和对照之间相关异质性变化的开创性研究。此外，NGF-p75NTR信号通路显著参与突触可塑性调节。这些发现为阐明辅酶q10在临床上糖尿病患者的DICD和联合用药中的潜在作用提供了细胞和分子证据。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.