Oluwatosin A Olayinka, Nicholas O'Neill, Jenny A Empawi, Payton Bock, Junming Hu, Hannah Rickner, Melissa Wong, Thor D Stein, Benjamin Wolozin, Lindsay A Farrer, Xiaoling Zhang
{"title":"单核RNA测序揭示了混合性阿尔茨海默病和血管病理中小胶质细胞和内皮细胞之间的关系。","authors":"Oluwatosin A Olayinka, Nicholas O'Neill, Jenny A Empawi, Payton Bock, Junming Hu, Hannah Rickner, Melissa Wong, Thor D Stein, Benjamin Wolozin, Lindsay A Farrer, Xiaoling Zhang","doi":"10.1016/j.nbd.2025.107128","DOIUrl":null,"url":null,"abstract":"<p><p>Single-nucleus RNA sequencing (snRNAseq) allows for the dissection of cell type-specific transcriptional profiles. We evaluated differential gene expression using snRNAseq data generated from hippocampal region tissue donated by 11 Boston University Alzheimer's Disease Research Center (BU-ADRC) participants with neuropathologically confirmed Alzheimer's disease (AD) with or without co-existing pathology (AD only = 3, AD+vascular disease (Vas) = 6, AD+Lewy body disease (LBD) = 2). Expression of 19,893 genes was compared between AD+Vas and other AD groups for each cell type. Co-expression modules were identified in a set of 174 bulk RNAseq hippocampal samples from BU-ADRC. Modules enriched in differentially expressed genes (DEGs) were identified using Fisher's exact tests. The overlap between DEGs and co-expression modules was incorporated into quantitative gene set analysis. AD+Vas subjects showed decreased expression of genes related to immune activation in microglia (t = -2.67, p = 2.72 × 10<sup>-2</sup>). Expression of these genes was negatively associated with expression of receptors P2RY12 and CX3CR1 (r = -0.87, p = 1.70 × 10<sup>-2</sup>), which have been linked to microglial migration and activation, respectively. Expression of genes that negatively regulate angiogenesis in endothelial cells was decreased (t = -4.84, p = 1.49 × 10<sup>-3</sup>) and associated with expression of the microglial activation genes in the BU-ADRC dataset (r = 0.68, p = 1.63 × 10<sup>-2</sup>). This association and the finding of upregulation of P2RY12 in AD+Vas samples were replicated in 393 ROSMAP Study dorsolateral prefrontal cortex snRNAseq samples (r = 0.34, p = 8.37 × 10<sup>-12</sup> and z = 5.82, p<sub>FDR</sub> = 8.73 × 10<sup>-6</sup>, respectively). In summary, we found an expression profile in brain tissue from individuals with AD+Vas pathology that is associated with reduced activation and increased migration in microglia and angiogenesis in endothelial cells.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107128"},"PeriodicalIF":5.6000,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Single nucleus RNA sequencing unveils relationship between microglia and endothelial cells in mixed Alzheimer's disease and vascular pathology.\",\"authors\":\"Oluwatosin A Olayinka, Nicholas O'Neill, Jenny A Empawi, Payton Bock, Junming Hu, Hannah Rickner, Melissa Wong, Thor D Stein, Benjamin Wolozin, Lindsay A Farrer, Xiaoling Zhang\",\"doi\":\"10.1016/j.nbd.2025.107128\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Single-nucleus RNA sequencing (snRNAseq) allows for the dissection of cell type-specific transcriptional profiles. We evaluated differential gene expression using snRNAseq data generated from hippocampal region tissue donated by 11 Boston University Alzheimer's Disease Research Center (BU-ADRC) participants with neuropathologically confirmed Alzheimer's disease (AD) with or without co-existing pathology (AD only = 3, AD+vascular disease (Vas) = 6, AD+Lewy body disease (LBD) = 2). Expression of 19,893 genes was compared between AD+Vas and other AD groups for each cell type. Co-expression modules were identified in a set of 174 bulk RNAseq hippocampal samples from BU-ADRC. Modules enriched in differentially expressed genes (DEGs) were identified using Fisher's exact tests. The overlap between DEGs and co-expression modules was incorporated into quantitative gene set analysis. AD+Vas subjects showed decreased expression of genes related to immune activation in microglia (t = -2.67, p = 2.72 × 10<sup>-2</sup>). Expression of these genes was negatively associated with expression of receptors P2RY12 and CX3CR1 (r = -0.87, p = 1.70 × 10<sup>-2</sup>), which have been linked to microglial migration and activation, respectively. Expression of genes that negatively regulate angiogenesis in endothelial cells was decreased (t = -4.84, p = 1.49 × 10<sup>-3</sup>) and associated with expression of the microglial activation genes in the BU-ADRC dataset (r = 0.68, p = 1.63 × 10<sup>-2</sup>). This association and the finding of upregulation of P2RY12 in AD+Vas samples were replicated in 393 ROSMAP Study dorsolateral prefrontal cortex snRNAseq samples (r = 0.34, p = 8.37 × 10<sup>-12</sup> and z = 5.82, p<sub>FDR</sub> = 8.73 × 10<sup>-6</sup>, respectively). In summary, we found an expression profile in brain tissue from individuals with AD+Vas pathology that is associated with reduced activation and increased migration in microglia and angiogenesis in endothelial cells.</p>\",\"PeriodicalId\":19097,\"journal\":{\"name\":\"Neurobiology of Disease\",\"volume\":\" \",\"pages\":\"107128\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurobiology of Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.nbd.2025.107128\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.nbd.2025.107128","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Single nucleus RNA sequencing unveils relationship between microglia and endothelial cells in mixed Alzheimer's disease and vascular pathology.
Single-nucleus RNA sequencing (snRNAseq) allows for the dissection of cell type-specific transcriptional profiles. We evaluated differential gene expression using snRNAseq data generated from hippocampal region tissue donated by 11 Boston University Alzheimer's Disease Research Center (BU-ADRC) participants with neuropathologically confirmed Alzheimer's disease (AD) with or without co-existing pathology (AD only = 3, AD+vascular disease (Vas) = 6, AD+Lewy body disease (LBD) = 2). Expression of 19,893 genes was compared between AD+Vas and other AD groups for each cell type. Co-expression modules were identified in a set of 174 bulk RNAseq hippocampal samples from BU-ADRC. Modules enriched in differentially expressed genes (DEGs) were identified using Fisher's exact tests. The overlap between DEGs and co-expression modules was incorporated into quantitative gene set analysis. AD+Vas subjects showed decreased expression of genes related to immune activation in microglia (t = -2.67, p = 2.72 × 10-2). Expression of these genes was negatively associated with expression of receptors P2RY12 and CX3CR1 (r = -0.87, p = 1.70 × 10-2), which have been linked to microglial migration and activation, respectively. Expression of genes that negatively regulate angiogenesis in endothelial cells was decreased (t = -4.84, p = 1.49 × 10-3) and associated with expression of the microglial activation genes in the BU-ADRC dataset (r = 0.68, p = 1.63 × 10-2). This association and the finding of upregulation of P2RY12 in AD+Vas samples were replicated in 393 ROSMAP Study dorsolateral prefrontal cortex snRNAseq samples (r = 0.34, p = 8.37 × 10-12 and z = 5.82, pFDR = 8.73 × 10-6, respectively). In summary, we found an expression profile in brain tissue from individuals with AD+Vas pathology that is associated with reduced activation and increased migration in microglia and angiogenesis in endothelial cells.
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.
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