Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell. 2024 Oct 3;187(20):5753-5774.e28. doi: 10.1016/j.cell.2024.08.019. Epub 2024 Sep 11.
The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.
要开发出成功的痴呆症疗法，需要了解人类大脑中这些疾病共有的和独特的分子特征。我们对阿尔茨海默病（AD）、额颞叶痴呆（FTD）和进行性核上性麻痹（PSP）进行了单核 RNA-seq 和 ATAC-seq 分析，对来自三个具有不同易感性和病理负担的脑区的 41 名参与者和大约 100 万个细胞（RNA+ATAC）进行了分析。我们鉴定出 32 种共享的、与疾病相关的细胞类型和 14 种疾病特异性的细胞类型。疾病特异性的细胞状态代表了影响 AD 中脑内 5 层神经元、FTD 中脑内 2/3 层神经元以及 PSP 中近投射神经元的神经胶质免疫机制和选择性神经元易损性。我们鉴定出与疾病相关的基因调控网络和受因果遗传风险影响的细胞，这些在不同的痴呆症中存在差异。这些数据说明了不同痴呆症中神经胶质和神经元组成和基因表达改变的异质性谱，并通过揭示共享和疾病特异性的细胞状态来确定治疗靶点。
