Single-nuclei transcriptome sequencing of mouse grey and white matter under myelin abnormalities

The aim of the dataset is to identify cell heterogeneity changes under myelin abnormalities. Alzheimer's disease (AD) is the most common form of dementia and neurodegenerative disease with increasing prevalence due to longer lifespan in the human population. Why aging constitutes the greatest risk factor for development of AD, however, remains poorly understood. Aging markedly affects oligodendrocytes and the structural integrity of their myelin sheaths which also causes secondary tissue inflammation. We propose a mechanistic link between aging-associated myelin dysfunction and the deposition of Amyloid-AB (AB) as primary neuropathological hallmark of early AD and hypothesized that breakdown of myelin - especially in cortical regions - is an upstream driver of amyloid deposition in AD. Here, we show that in transgenic mouse models of AD, genetically induced myelin defects by Cnp or Plp1 depletion, as well as direct demyelination are potent drivers of amyloid deposition in vivo as shown by light sheet microscopy imaging. At transcriptomic level, bulk and single-cell RNA sequencing revealed successfully induced disease-associated-microglia (DAM)-like phenotypes in Cnp-/- animals. These activated microglia, however, are primarily engaged with myelin seemingly preventing the protective reactions of the microglia pool to AB plaques. Our work, therefore, identifies myelin aging as a previously overlooked risk factor for AD and makes the case for myelin health-directed therapies in AD. Cortex and corpus callosum were dissected from every two animals (3-month-old) and pooled into one sample for single-nuclei RNA sequencing using 10x genomics Chromium 3' assay. Each genotype has 2 replicates (in total n=4 animals).本数据集旨在探究髓鞘异常状态下的细胞异质性变化。阿尔茨海默病（Alzheimer's disease, AD）是最常见的痴呆及神经退行性疾病，其患病率随人类预期寿命延长持续攀升。然而，衰老为何是AD发病的最大风险因素，目前仍不甚明晰。衰老会显著影响少突胶质细胞及其髓鞘的结构完整性，进而引发继发性组织炎症。我们提出了衰老相关髓鞘功能障碍与作为AD早期主要神经病理特征的β淀粉样蛋白（Amyloid-AB, AB）沉积之间的机制性关联，并假设髓鞘崩解——尤其是皮层区域的髓鞘崩解——是AD中淀粉样蛋白沉积的上游驱动因素。本研究在AD转基因小鼠模型中证实，通过敲除Cnp或Plp1基因诱导的遗传性髓鞘缺陷，以及直接诱导脱髓鞘，均可在体内有效促进淀粉样蛋白沉积，该结果通过光片显微镜成像得到验证。在转录组层面，批量RNA测序与单细胞RNA测序结果显示，Cnp基因敲除（Cnp-/-）小鼠体内成功诱导出了疾病相关小胶质细胞（disease-associated-microglia, DAM）样表型。然而，这些活化的小胶质细胞主要与髓鞘相关，似乎阻碍了小胶质细胞群对AB斑块的保护性反应。因此，本研究将髓鞘衰老鉴定为此前被忽视的AD风险因素，并支持针对髓鞘健康的AD治疗策略。本实验从每两只3月龄小鼠体内分离皮层与胼胝体组织，混合为一个样本，采用10x Genomics Chromium 3'端测序技术开展单细胞核RNA测序。每个基因型设置2个生物学重复，总实验动物数为n=4。