Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong, Chongqing, 400016, China.
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Cell Mol Neurobiol. 2024 Feb 12;44(1):20. doi: 10.1007/s10571-024-01453-w.
Alzheimer disease (AD) is an irreversible neurodegenerative disease, and astrocytes play a key role in its onset and progression. The aim of this study is to analyze the characteristics of neurotoxic astrocytes and identify novel molecular targets for slowing down the progression of AD. Single-nucleus RNA sequencing (snRNA-seq) data were analyzed from various AD cohorts comprising about 210,654 cells from 53 brain tissue. By integrating snRNA-seq data with bulk RNA-seq data, crucial astrocyte types and genes associated with the prognosis of patients with AD were identified. The expression of neurotoxic astrocyte markers was validated using 5 × FAD and wild-type (WT) mouse models, combined with experiments such as western blot, quantitative real-time PCR (qRT-PCR), and immunofluorescence. A group of neurotoxic astrocytes closely related to AD pathology was identified, which were involved in inflammatory responses and pathways related to neuron survival. Combining snRNA and bulk tissue data, ZEP36L, AEBP1, WWTR1, PHYHD1, DST and RASL12 were identified as toxic astrocyte markers closely related to disease severity, significantly elevated in brain tissues of 5 × FAD mice and primary astrocytes treated with Aβ. Among them, WWTR1 was significantly increased in astrocytes of 5 × FAD mice, driving astrocyte inflammatory responses, and has been identified as an important marker of neurotoxic astrocytes. snRNA-seq analysis reveals the biological functions of neurotoxic astrocytes. Six genes related to AD pathology were identified and validated, among which WWTR1 may be a novel marker of neurotoxic astrocytes.
阿尔茨海默病（AD）是一种不可逆转的神经退行性疾病，星形胶质细胞在其发病和进展中起着关键作用。本研究旨在分析神经毒性星形胶质细胞的特征，并确定新的分子靶点，以减缓 AD 的进展。对来自 53 个脑组织的约 210654 个细胞的各种 AD 队列的单细胞 RNA 测序（snRNA-seq）数据进行了分析。通过将 snRNA-seq 数据与批量 RNA-seq 数据整合，确定了与 AD 患者预后相关的关键星形胶质细胞类型和基因。使用 5×FAD 和野生型（WT）小鼠模型，结合 Western blot、定量实时 PCR（qRT-PCR）和免疫荧光等实验，验证了神经毒性星形胶质细胞标志物的表达。鉴定出一组与 AD 病理学密切相关的神经毒性星形胶质细胞，这些细胞参与了炎症反应和与神经元存活相关的途径。结合 snRNA 和批量组织数据，确定了 ZEP36L、AEBP1、WWTR1、PHYHD1、DST 和 RASL12 是与疾病严重程度密切相关的毒性星形胶质细胞标志物，在 5×FAD 小鼠和 Aβ 处理的原代星形胶质细胞的脑组织中显著升高。其中，WWTR1 在 5×FAD 小鼠的星形胶质细胞中显著增加，驱动星形胶质细胞炎症反应，已被确定为神经毒性星形胶质细胞的重要标志物。snRNA-seq 分析揭示了神经毒性星形胶质细胞的生物学功能。鉴定并验证了 6 个与 AD 病理相关的基因，其中 WWTR1 可能是神经毒性星形胶质细胞的一个新标志物。
