Single-nucleus RNA sequencing reveals transcriptional changes of hippocampal neurons in APP23 mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that mostly strikes the elderly. However, the exact molecular and cellular pathogenesis of AD, especially the dynamic changes of neurons during disease progression, remains poorly understood. Here we used single-nucleus RNA sequencing (snRNA-seq) to access the transcriptional changes of hippocampal neurons in APP23 mouse model of AD. We performed snRNA-seq using a modified Smart-seq2 technique on 3,280 neuronal nuclei from the hippocampus of young and aged APP23 and control mice and identified four distinct subpopulations. Comparative transcriptional analysis showed multiple changes in different subtypes of hippocampal neurons of APP23 mice in comparison to control mice, as well as the transcriptional changes in these neurons during disease progression. Our findings revealed multiple neuronal subtype-specific transcriptional changes that may lead to targets for future studies of AD. Single-nucleus RNA-seq for identifying the transcriptional changes in hippocampal neurons of an Alzheimer’s disease mouse model.

阿尔茨海默病（Alzheimer’s disease, AD）是一种主要累及老年群体的进行性神经退行性疾病。目前，AD的确切分子与细胞发病机制，尤其是疾病进展过程中神经元的动态变化，仍知之甚少。本研究以阿尔茨海默病APP23小鼠模型为研究对象，采用单细胞核RNA测序（single-nucleus RNA sequencing, snRNA-seq）技术探究其海马神经元的转录组变化。我们通过改良的Smart-seq2技术，对年轻、老年APP23模型小鼠及对照小鼠的海马组织中分离得到的3280个神经元细胞核开展单细胞核RNA测序，最终鉴定出4个特征各异的神经元亚群。比较转录组分析结果显示，与对照小鼠相比，APP23模型小鼠的海马神经元各亚型存在多项转录水平改变；同时也揭示了疾病进程中此类神经元的转录组动态变化。本研究发现了多种神经元亚型特异性的转录组改变，可为未来阿尔茨海默病的相关研究提供潜在靶点。本研究通过单细胞核RNA测序技术，明确了阿尔茨海默病小鼠模型中海马神经元的转录组变化。