Shao Fanghong, Wang Meiting, Guo Qi, Zhang Bowen, Wang Xiangting
Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, China.
Front Aging Neurosci. 2021 Nov 8;13:742176. doi: 10.3389/fnagi.2021.742176. eCollection 2021.
The detailed characteristics of neuronal cell populations in Alzheimer's disease (AD) using single-cell RNA sequencing have not been fully elucidated. To explore the characterization of neuronal cell populations in AD, this study utilized the publicly available single-nucleus RNA-sequencing datasets in the transgenic model of 5X familial Alzheimer's disease (5XFAD) and wild-type mice to reveal an AD-associated excitatory neuron population (C3:Ex.Neuron). The relative abundance of C3:Ex.Neuron increased at 1.5 months and peaked at 4.7 months in AD mice. Functional pathways analyses showed that the pathways positively related to neurodegenerative disease progression were downregulated in the C3:Ex.Neuron at 1.5 months in AD mice. Based on the differentially expressed genes among the C3:Ex.Neuron, four subtypes (C3.1-4) were identified, which exhibited distinct abundance regulatory patterns during the development of AD. Among these subtypes, the C3.1 neurons [marked by netrin G1 (Ntng1)] exhibited a similar regulatory pattern as the C3:Ex.Neuron in abundance during the development of AD. In addition, our gene set variation analysis (GSEA) showed that the C3.1 neurons, instead of other subtypes of the C3:Ex.Neuron, possessed downregulated AD pathways at an early stage (1.5 months) of AD mice. Collectively, our results identified a previously unidentified subset of excitatory neurons and provide a potential application of these neurons to modulate the disease susceptibility.
利用单细胞RNA测序对阿尔茨海默病（AD）中神经元细胞群体的详细特征尚未完全阐明。为了探索AD中神经元细胞群体的特征，本研究利用5X家族性阿尔茨海默病（5XFAD）转基因模型和野生型小鼠中公开可用的单核RNA测序数据集，以揭示与AD相关的兴奋性神经元群体（C3：Ex.Neuron）。在AD小鼠中，C3：Ex.Neuron的相对丰度在1.5个月时增加，并在4.7个月时达到峰值。功能通路分析表明，与神经退行性疾病进展呈正相关的通路在AD小鼠1.5个月时的C3：Ex.Neuron中被下调。基于C3：Ex.Neuron中差异表达的基因，鉴定出四种亚型（C3.1 - 4），它们在AD发展过程中表现出不同的丰度调节模式。在这些亚型中，C3.1神经元[以netrin G1（Ntng1）为标记]在AD发展过程中的丰度调节模式与C3：Ex.Neuron相似。此外，我们的基因集变异分析（GSEA）表明，在AD小鼠的早期阶段（1.5个月），是C3.1神经元而非C3：Ex.Neuron的其他亚型具有下调的AD通路。总体而言；我们的结果鉴定出了一个先前未被识别的兴奋性神经元亚群，并为这些神经元在调节疾病易感性方面的潜在应用提供了依据。
