Altered gene expression in excitatory neurons is associated with Alzheimer's disease and its higher incidence in women.
Altered gene expression in excitatory neurons is associated with Alzheimer's disease and its higher incidence in women.
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DOI：
10.1002/trc2.12373
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发表时间：
2023-01
影响因子：
4.8
通讯作者：
Schaffer, Alejandro A
中科院分区：
文献类型：
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作者：
Garcia, A Xavier;Xu, Jielin;Cheng, Feixiong;Ruppin, Eytan;Schaffer, Alejandro A
阿尔茨海默病（AD）是一种神经退行性疾病，涉及大脑中不同细胞类型之间的相互作用。先前的单细胞和大细胞表达阿尔茨海默病研究报告了在该疾病中主要改变表达的关键细胞类型和细胞途径的相互矛盾的发现。我们以统一、连贯的方式重新分析了这些数据，旨在解决和扩展过去的发现。我们的分析揭示了女性AD发病率高于男性的观察结果。我们重新分析了三个单细胞转录组学数据集。我们使用软件基于模型的单细胞转录组学分析（MAST）来寻找AD病例与匹配对照的差异表达基因，并将两性和两性分开进行比较。我们使用GOrilla软件在差异表达基因中寻找富集通路。由于男性/女性发病率的差异，我们研究了X染色体上的基因，重点研究了假常染色体区域（PAR）的基因以及在个体或组织中异质的X -失活基因。我们通过分析基因表达Omnibus中来自皮质的大量AD数据集来验证研究结果。我们的研究结果解决了文献中的一个矛盾，表明通过将AD患者与未受影响的对照组进行比较，兴奋性神经元比其他细胞类型具有更多的差异表达基因。兴奋性神经元的性别特异性分析改变了突触传递和相关通路。PAR基因和X染色体异质基因，例如BEX1和ELK1，可能导致阿尔茨海默病的性别发病率差异。在所有三个单细胞数据集中，与对照组相比，GRIN1在病例中作为常染色体基因过度表达，并且在病例中作为功能候选基因有助于途径上调。综上所述，这些结果指出了两个关于阿尔茨海默病发病机制的长期问题之间的潜在联系，包括哪种细胞类型最重要以及为什么女性比男性发病率更高。通过重新分析三个已发表的单细胞RNAseq数据集，我们解决了文献中的一个矛盾，并表明当将AD患者与未受影响的对照组进行比较时，兴奋性神经元比其他细胞类型具有更多的差异表达基因。对已发表的单细胞数据集的进一步分析表明，在兴奋性神经元的性别特异性分析中，突触传递和相关通路发生了改变。结合对单细胞数据集和公开的大量转录组学数据集的分析显示，X染色体基因，如BEX1、ELK1和USP11，其X -失活状态是异质性的，可能导致女性阿尔茨海默病的发病率较高。
Alzheimer's disease (AD) is a neurodegenerative disorder involving interactions between different cell types in the brain. Previous single‐cell and bulk expression Alzheimer's studies have reported conflicting findings about the key cell types and cellular pathways whose expression is primarily altered in this disease. We re‐analyzed these data in a uniform, coherent manner aiming to resolve and extend past findings. Our analysis sheds light on the observation that females have higher AD incidence than males. We re‐analyzed three single‐cell transcriptomics datasets. We used the software Model‐based Analysis of Single‐cell Transcriptomics (MAST) to seek differentially expressed genes comparing AD cases to matched controls for both sexes together and each sex separately. We used the GOrilla software to search for enriched pathways among the differentially expressed genes. Motivated by the male/female difference in incidence, we studied genes on the X‐chromosome, focusing on genes in the pseudoautosomal region (PAR) and on genes that are heterogeneous across individuals or tissues for X‐inactivation. We validated findings by analyzing bulk AD datasets from the cortex in the Gene Expression Omnibus. Our results resolve a contradiction in the literature, showing that by comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do other cell types. Synaptic transmission and related pathways are altered in a sex‐specific analysis of excitatory neurons. PAR genes and X‐chromosome heterogeneous genes, including, for example, BEX1 and ELK1, may contribute to the difference in sex incidence of Alzheimer's disease. GRIN1, stood out as an overexpressed autosomal gene in cases versus controls in all three single‐cell datasets and as a functional candidate gene contributing to pathways upregulated in cases. Taken together, these results point to a potential linkage between two longstanding questions concerning AD pathogenesis, involving which cell type is the most important and why females have a higher incidence than males. By reanalyzing three, published, single‐cell RNAseq datasets, we resolved a contradiction in the literature and showed that when comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do other cell types. Further analysis of the published single‐cell datasets showed that synaptic transmission and related pathways are altered in a sex‐specific analysis of excitatory neurons. Combining analysis of single‐cell datasets and publicly available bulk transcriptomics datasets revealed that X‐chromosome genes, such as BEX1, ELK1, and USP11, whose X‐inactivation status is heterogeneous may contribute to the higher incidence in females of Alzheimer's disease.