Department of Biomedical Sciences, Section Molecular Neurobiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
J Neurosci Res. 2024 Mar;102(3):e25295. doi: 10.1002/jnr.25295.
Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from male APPswe/PS1dE9 (APP/PS1) mice and wild-type littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single-cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentially reflect the initial response of microglia to Aβ.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是痴呆症最常见的病因，其特征是细胞外淀粉样β（Aβ）聚集物和神经元内过度磷酸化的 Tau 的沉积。在全基因组关联研究（GWAS）中鉴定出的许多 AD 风险基因在小胶质细胞中表达，小胶质细胞是中枢神经系统的固有免疫细胞。与 AD 病理学相关的特定小胶质细胞亚型出现，例如与疾病相关的小胶质细胞（DAMs），在淀粉样小鼠模型和人类 AD 病例中，其数量随年龄增长而增加。然而，这些小胶质细胞对淀粉样蛋白的初始转录变化仍不清楚。在这里，为了确定小胶质细胞基因表达的早期变化，从雄性 APPswe/PS1dE9（APP/PS1）小鼠和野生型同窝仔鼠的海马小胶质细胞中分离出来，并通过 RNA 测序（RNA-seq）进行分析。通过 bulk RNA-seq，在 6 个月大的 APP/PS1 小鼠的海马小胶质细胞中检测到转录组变化。通过对 6 个月大的 APP/PS1 小鼠的 CD11c 阳性和阴性小胶质细胞进行单细胞 RNA-seq，并对从稳态到 CD11c 阳性小胶质细胞的转录轨迹进行分析，我们确定了一组可能反映小胶质细胞对 Aβ 初始反应的基因。
