Laboratory Animal Department, Kunming Medical University, Kunming 650500, Yunnan, China.
Dermatology Department of Xiangya Hospital, Central South University, Changsha, China.
Exp Gerontol. 2024 Sep;194:112512. doi: 10.1016/j.exger.2024.112512. Epub 2024 Jul 10.
OBJECTIVE: This study investigated sex-specific pathogenesis mechanisms in Alzheimer's disease (AD) using single-nucleus RNA sequencing (snRNA-seq) data. METHODS: Data from the Gene Expression Omnibus (GEO) were searched using terms "Alzheimer's Disease", "single cell", and "Homo sapiens". Studies excluding APOE E4 and including comprehensive gender information with 10× sequencing methods were selected, resulting in GSE157827 and GSE174367 datasets from human prefrontal cortex samples. Sex-stratified analyses were conducted on these datasets, and the outcomes of the analysis for GSE157827 were compared with those of GSE174367. The findings were validated using expression profiling from the mouse dataset GSE85162. Furthermore, real-time PCR experiments in mice further confirmed these findings. The Seurat R package was used to identify cell types, and batch effects were mitigated using the Harmony R package. Cell proportions by sex were compared using the Mann-Whitney-Wilcoxon test, and gene expression variability was displayed with an empirical cumulative distribution plot. Differentially expressed genes were identified using the FindMarkers function with the MAST test. Transcription factors were analyzed using the RcisTarget R package. RESULTS: Seven cell types were identified: astrocytes, endothelial cells, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, and oligodendrocyte progenitor cells. Additionally, five distinct subpopulations of both endothelial and microglial cells were also identified, respectively. Key findings included: (1) In endothelial cells, genes involved in synapse organization, such as Insulin Like Growth Factor 1 Receptor (IGF1R) and Fms Related Receptor Tyrosine Kinase 1(FLT1), showed higher expression in females with AD. (2) In microglial cells, genes in the ribosome pathway exhibited higher expression in males without AD compared to females (with or without AD) and males with AD. (3) Chromodomain Helicase DNA Binding Protein 2 (CHD2) negatively regulated gene expression in the ribosome pathway in male microglia, suppressing AD, this finding was further validated in mice. (4) Differences between Asians and Caucasians were observed based on sex and disease status stratification. CONCLUSIONS: IGF1R and FLT1 in endothelial cells contribute to AD in females, while CHD2 negatively regulates ribosome pathway gene expression in male microglia, suppressing AD in humans and mice.
目的：本研究使用单细胞 RNA 测序（snRNA-seq）数据探讨阿尔茨海默病（AD）的性别特异性发病机制。
方法：使用术语“阿尔茨海默病”、“单细胞”和“智人”在基因表达综合数据库（GEO）中搜索数据。选择排除 APOE E4 并包含全面性别信息的 10× 测序方法的研究，得到来自人类前额叶皮层样本的 GSE157827 和 GSE174367 数据集。对这些数据集进行性别分层分析，并比较 GSE157827 分析结果与 GSE174367 的结果。使用来自小鼠数据集 GSE85162 的表达谱进行验证。此外，在小鼠中进行实时 PCR 实验进一步证实了这些发现。使用 Seurat R 包识别细胞类型，并使用 Harmony R 包减轻批次效应。使用 Mann-Whitney-Wilcoxon 检验比较性别细胞比例，使用经验累积分布图显示基因表达变异性。使用 MAST 检验的 FindMarkers 函数识别差异表达基因。使用 RcisTarget R 包分析转录因子。
结果：鉴定出 7 种细胞类型：星形胶质细胞、内皮细胞、兴奋性神经元、抑制性神经元、小胶质细胞、少突胶质细胞和少突胶质细胞前体细胞。此外，还分别鉴定出内皮细胞和小胶质细胞的 5 个不同亚群。主要发现包括：（1）在内皮细胞中，参与突触组织的基因，如胰岛素样生长因子 1 受体（IGF1R）和 Fms 相关受体酪氨酸激酶 1（FLT1），在 AD 女性中表达更高。（2）在小胶质细胞中，核糖体途径中的基因在无 AD 的男性中表达高于女性（无论是否患有 AD）和患有 AD 的男性。（3）染色质解旋酶 DNA 结合蛋白 2（CHD2）在雄性小胶质细胞中负调控核糖体途径中的基因表达，抑制 AD，这一发现进一步在小鼠中得到验证。（4）根据性别和疾病状态分层，观察到亚洲人和高加索人之间的差异。
结论：内皮细胞中的 IGF1R 和 FLT1 导致女性 AD，而 CHD2 负调控雄性小胶质细胞中核糖体途径基因的表达，抑制人类和小鼠的 AD。
Mol Neurodegener. 2023-6-20
Proc Natl Acad Sci U S A. 2020-9-28
Pharmaceuticals (Basel). 2022-9-22
Curr Alzheimer Res. 2025-4-28
Zotero 插件