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Abstract：
Typical differential single-nucleus gene expression (snRNA-seq) analyses in Alzheimer\'s disease (AD) provide fixed snapshots of cellular alterations, making the accurate detection of temporal cell changes challenging. To characterize the dynamic cellular and transcriptomic differences in AD neuropathology, we apply the novel concept of RNA velocity to the study of single-nucleus RNA from the cortex of 60 subjects with varied levels of AD pathology. RNA velocity captures the rate of change of gene expression by comparing intronic and exonic sequence counts. We performed differential analyses to find the significant genes driving both cell type-specific RNA velocity and expression differences in AD, extensively compared these two transcriptomic metrics, and clarified their associations with multiple neuropathologic traits. The results were cross-validated in an independent dataset. Comparison of AD pathology-associated RNA velocity with parallel gene expression differences reveals sets of genes and molecular pathways that underlie the dynamic and static regimes of cell type-specific dysregulations underlying the disease. Differential RNA velocity and its linked progressive neuropathology point to significant dysregulations in synaptic organization and cell development across cell types. Notably, most of the genes underlying this synaptic dysregulation showed increased RNA velocity in AD subjects compared to controls. Accelerated cell changes were also observed in the AD subjects, suggesting that the precocious depletion of precursor cell pools might be associated with neurodegeneration. Overall, this study uncovers active molecular drivers of the spatiotemporal alterations in AD and offers novel insights towards gene- and cell-centric therapeutic strategies accounting for dynamic cell perturbations and synaptic disruptions.
摘要：
阿尔茨海默病（AD）中典型的差异单核基因表达（snRNA-seq）分析提供了细胞改变的固定快照，使准确检测时间细胞变化具有挑战性。为了表征AD神经病理学中动态的细胞和转录组差异，我们将RNA速度的新概念应用于60名AD病理水平不同的受试者的皮质中的单核RNA的研究。RNA速度通过比较内含子和外显子序列计数来捕获基因表达的变化率。我们进行了差异分析，以发现在AD中驱动细胞类型特异性RNA速度和表达差异的重要基因。广泛比较了这两个转录组指标，并阐明了它们与多种神经病理学特征的关联。结果在独立的数据集中进行交叉验证。AD病理相关的RNA速度与平行基因表达差异的比较揭示了构成疾病基础的细胞类型特异性失调的动态和静态机制的基因和分子途径集。差异RNA速度及其相关的进行性神经病理学表明，跨细胞类型的突触组织和细胞发育中的显着失调。值得注意的是,与对照组相比，这种突触失调背后的大多数基因在AD受试者中显示出增加的RNA速度。在AD受试者中也观察到加速的细胞变化，表明前体细胞池的早熟消耗可能与神经变性有关。总的来说,这项研究揭示了AD时空改变的活性分子驱动因素，并为解释动态细胞扰动和突触破坏的以基因和细胞为中心的治疗策略提供了新的见解。
