Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
Medical Scientist Training Program, Baylor College of Medicine, Houston, United States.
Elife. 2023 May 23;12:e85251. doi: 10.7554/eLife.85251.
Aging is a major risk factor for Alzheimer's disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell-type-specific transcriptional patterns between and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.
衰老是阿尔茨海默病（AD）的一个主要风险因素，细胞类型的脆弱性是其特征性临床表现的基础。我们对具有人类 tau 全神经元表达的进行了纵向单细胞 RNA 测序，tau 形成 AD 神经纤维缠结病理学。虽然 tau 和衰老诱导的基因表达有很强的重叠（93%），但它们在受影响的细胞类型上有所不同。与衰老的广泛影响相比，tau 触发的变化强烈极化到兴奋性神经元和神经胶质细胞。此外，tau 可以以细胞类型特异性的方式激活或抑制固有免疫基因表达特征。细胞丰度和基因表达的整合将神经元中的核因子 kappa B 信号作为细胞脆弱性的标志物。我们还强调了在 和人类死后脑组织之间细胞类型特异性转录模式的保守性。总的来说，我们的结果为在 tau 病的遗传上可处理的模型中以细胞分辨率解析动态、年龄依赖性基因表达变化创建了一个资源。
