Department of Quantitative Health Sciences, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 55905, USA.
Sci Rep. 2023 Oct 6;13(1):16855. doi: 10.1038/s41598-023-44183-7.
Mounting evidence highlights the crucial role of aging in the pathogenesis of Alzheimer's disease (AD). We have previously explored human apoE-targeted replacement mice across different ages and identified distinct molecular pathways driven by aging. However, the specific contribution of different brain cell types to the gene modules underlying these pathways remained elusive. To bridge this knowledge gap, we employed a computational deconvolution approach to examine cell-type-specific gene expression profiles in major brain cell types, including astrocytes (AS), microglia (MG), oligodendroglia (OG), neurons (NEU), and vascular cells (VC). Our findings revealed that immune module genes were predominantly expressed in MG, OG, and VC. The lipid metabolism module genes were primarily expressed in AS, MG, and OG. The mitochondria module genes showed prominent expression in VC, and the synapse module genes were primarily expressed in NEU and VC. Furthermore, we identified intra- and inter-cell-type interactions among these module genes and validated their aging-associated expression changes using published single cell studies. Our study dissected bulk brain transcriptomics data at the cellular level, providing a closer examination of the cell-type contributions to the molecular pathways driven by aging.
越来越多的证据强调了衰老在阿尔茨海默病（AD）发病机制中的关键作用。我们之前研究了不同年龄的人类载脂蛋白 E 靶向替代小鼠，并确定了由衰老驱动的不同分子途径。然而，不同脑细胞类型对这些途径下潜在基因模块的具体贡献仍然难以捉摸。为了弥补这一知识空白，我们采用了一种计算去卷积方法来研究主要脑细胞类型（包括星形胶质细胞（AS）、小胶质细胞（MG）、少突胶质细胞（OG）、神经元（NEU）和血管细胞（VC））中的细胞类型特异性基因表达谱。我们的研究结果表明，免疫模块基因主要在 MG、OG 和 VC 中表达。脂质代谢模块基因主要在 AS、MG 和 OG 中表达。线粒体模块基因在 VC 中表达明显，突触模块基因主要在 NEU 和 VC 中表达。此外，我们还鉴定了这些模块基因之间的细胞内和细胞间相互作用，并使用已发表的单细胞研究验证了它们与衰老相关的表达变化。我们的研究在细胞水平上对大脑转录组数据进行了剖析，更深入地研究了细胞类型对衰老驱动的分子途径的贡献。
