Differences in transcriptome characteristics and drug repositioning of Alzheimer's disease according to sex

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease Pub Date : 2025-04-10 DOI:10.1016/j.nbd.2025.106909

Jingqi Shi , Minghua Zhang , Yazhuo Hu , Jing Liu , Ke Li , Xuan Sun , Siyu Chen , Jianwei Liu , Ling Ye , Jiao Fan , Jianjun Jia

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引用次数: 0

Abstract

Background

Previous studies have shown significant sex differences in AD with regarding its epidemiology, pathophysiology, clinical presentation, and treatment response. However, the transcriptome variances associated with sex in AD remain unclear.

Methods

RNA sequencing (RNA-seq) and transcriptomic analyses were performed on peripheral blood samples from total of 54 patients, including male AD patients (n = 15), female AD patients (n = 10), male MCI patients (n = 7), female MCI patients (n = 11), male healthy controls (n = 6), female healthy controls (n = 5). The snRNA-seq dataset (GSE167494, GSE157827) of prefrontal cortex tissues was obtained from the Gene Expression Omnibus (GEO). We conducted an investigation into differentially expressed genes and pathways in the peripheral blood cells as well as prefrontal cortex tissues of both male and female AD patients with consideration to sex-related factors. Additionally, we analyzed the distribution and characteristics of cells in the cerebral cortex as well as the interaction and communication between cells of male and female AD patients. Connectivity Map (CMap) was utilized for predicting and screening potential sex-specific drugs for AD.

Results

The transcriptome profile and associated biological processes in the peripheral blood of male and female AD and MCI patients exhibit discernible differences, including upregulation of BASP1 in AD male patients and arousing TNS1 in AD female patients. The distribution of various cell types in the prefrontal cortex tissues differs between male and female AD patients, like neuron and oligodendrocyte decreased and endothelial cell and astrocyte increased in female compared with male, while a multitude of genes exhibit significant differential expression. The results of cell communication analysis, such as collagen signaling pathway, suggest that sex disparities impact intercellular interactions within prefrontal cortex tissues among individuals with AD. By drug repositioning, several drugs, including torin-2 and YM-298198, might have the potential to therapeutic value of MCI or AD, while drugs like homoharringtonine and teniposide have potential opposite effects in different sexes.

Conclusion

The characteristics of the transcriptome in peripheral blood and single-cell transcriptome in the prefrontal cortex exhibit significant differences between male and female patients with AD, which providing a basis for future sex stratified treatment of AD.

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阿尔茨海默病转录组特征和药物重新定位的性别差异

背景以往的研究表明，在AD的流行病学、病理生理、临床表现和治疗反应方面存在显著的性别差异。然而，阿尔茨海默病中与性别相关的转录组差异仍不清楚。方法对54例AD男性患者（15例）、AD女性患者（10例）、MCI男性患者（7例）、MCI女性患者（11例）、健康对照男性患者（6例）、健康对照女性患者（5例）的外周血样本进行srna测序（RNA-seq）和转录组学分析，并从Gene Expression Omnibus （GEO）获取前额皮质组织snRNA-seq数据集（GSE167494、GSE157827）。我们在考虑性别相关因素的情况下，对男女AD患者外周血和前额皮质组织中差异表达的基因和通路进行了研究。此外，我们还分析了男性和女性AD患者大脑皮层细胞的分布和特征以及细胞之间的相互作用和通讯。连接图（CMap）用于预测和筛选潜在的性别特异性AD药物。结果男性和女性AD和MCI患者的外周血转录组谱和相关生物学过程存在明显差异，包括男性AD患者BASP1上调，女性AD患者TNS1上调。男性和女性AD患者前额叶皮层组织中各种细胞类型的分布存在差异，女性神经元和少突胶质细胞较男性减少，内皮细胞和星形胶质细胞较男性增加，同时许多基因表现出明显的差异表达。细胞通讯分析的结果，如胶原信号通路，表明性别差异影响阿尔茨海默病患者前额皮质组织内的细胞间相互作用。通过药物重新定位，torin-2和YM-298198等几种药物可能对MCI或AD具有潜在的治疗价值，而homharkingtonine和teniposide等药物在不同性别中具有潜在的相反作用。结论AD患者外周血转录组和前额叶皮层单细胞转录组特征在男女AD患者中存在显著差异，为今后AD的性别分层治疗提供了依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurobiology of Disease 医学-神经科学

CiteScore

11.20

自引率

3.30%

发文量

270

审稿时长

76 days

期刊介绍： Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.