基础医学与临床 ›› 2025, Vol. 45 ›› Issue (7): 841-850.doi: 10.16352/j.issn.1001-6325.2025.07.0841

• 研究论文 • 上一篇    下一篇

人脑单细胞数据揭示癫痫与阿尔茨海默病共有突触功能障碍及免疫异常

于晓琳, 张而宁, 沙龙泽*   

  1. 中国医学科学院基础医学研究所 北京协和医学院基础学院 重大疾病共性机制研究全国重点实验室,北京 100005
  • 收稿日期:2025-03-28 修回日期:2025-04-23 出版日期:2025-07-05 发布日期:2025-06-24
  • 通讯作者: *shalz_pumc@163.com
  • 基金资助:
    国家重点研发计划(2020YFA0804502); 国家自然科学基金(82171447)

Human brain single-cell data reveal shared synaptic dysfunction and immune abnormality in epilepsy and Alzheimer′s disease

YU Xiaolin, ZHANG Erning, SHA Longze*   

  1. State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences CAMS, School of Basic Medicine PUMC, Beijing 100005, China
  • Received:2025-03-28 Revised:2025-04-23 Online:2025-07-05 Published:2025-06-24
  • Contact: *shalz_pumc@163.com

摘要: 目的 利用公开的人脑单细胞转录组测序数据,鉴定阿尔茨海默病(AD)与癫痫之间的共表达基因及其潜在共病机制,并在表达嵌合小鼠/人淀粉样蛋白前体蛋白(Mo/HuAPP695swe)和突变人早老蛋白1(PS1-dE9)的APP/PS1双转基因AD模型小鼠中验证。方法 选取基因表达综合(GEO)数据库中AD和癫痫患者的脑组织单细胞转录组测序数据,利用Seurat与clusterProfiler等R语言工具进行细胞聚类、差异表达分析与基因本体论(GO)功能富集分析,并进行视频脑电图(vEEG)检测和Western blot实验。结果 共识别出8种脑细胞类型,其中神经元和胶质细胞在AD与癫痫中存在共有的差异表达基因。GO功能富集分析发现,这些基因聚类于金属离子反应、突触传递、氧化应激和免疫激活等通路,提示两种疾病可能在突触功能障碍与炎性反应应答等方面存在共同病理基础。利用APP/PS1的AD小鼠模型,通过vEEG记录发现30%小鼠表现出高频率的癫痫发作,70%小鼠表现出低频率的癫痫发作。在AD小鼠前额叶皮质中也验证出单细胞测序数据鉴别出的关键分子HES5、c-FOS及RPL10A的表达上调。结论 AD与癫痫在特定细胞类型中存在基因共表达谱及功能通路,为进一步阐明其共病机制与开发靶向干预策略提供了理论支持。

关键词: 单细胞转录组测序, 荟萃分析, 共病机制, APP/PS1双转基因小鼠

Abstract: Objective To identify co-expressed genes and potential comorbidity mechanisms between Alzheimer′s disease(AD) and epilepsy with publicly available single-cell transcriptome sequencing data from human brains, followed by functional validation in APP/PS1 double transgenic AD mouse models expressing the chimerical Mo/HuAPP695swe amyloid precursor protein and mutant PS1-dE9 presenilin 1. Methods The single-cell transcriptome sequencing data of brain tissue from AD and epilepsy patients were collected from gene expression omnibus (GEO) database followed by cell clustering, differential expression analysis and gene ontology (GO)functional enrichment analysis using R-based tools such as Seurat and cluster Profiler and video electroencephalogram (vEEG) monitoring and Western blot experiments. Results A total of eight major brain cell types were identified, with neurons and glial cells exhibiting shared differentially expressed genes between AD and epilepsy. These co-expressed genes were significantly clustered in pathways related to metal ion homeostasis, synaptic transmission, oxidative stress, and immune activation, which suggested common pathological mechanisms involving in synaptic dysfunction and neuro-inflammation in both disorders. The vEEG recordings of APP/PS1 mouse model of AD showed 30% of mice exhibited high-frequency epileptic seizures, while 70% showed low-frequency seizure activity. Subsequent validation in the prefrontal cortex of AD mice confirmed up-regulated expression of key molecular markers (HES5, c-FOS, and RPL10A) identified through single-cell sequencing analysis. Conclusions AD and epilepsy share gene co-expression profiles and functional pathways in specific cell types. The results of research provide a theoretical support for further elucidating their comorbidity mechanisms and developing targeted therapeutic strategy.

Key words: single-cell transcriptome sequencing, Meta-analysis, comorbid mechanisms, APP/PS1 double transgenic mouse

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