The Jackson Laboratory, Bar Harbor, ME 04609, USA.
The Jackson Laboratory, Bar Harbor, ME 04609, USA; Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
Cell Rep. 2021 Feb 9;34(6):108739. doi: 10.1016/j.celrep.2021.108739.
Genetic and genome-wide association studies suggest a central role for microglia in Alzheimer's disease (AD). However, single-cell RNA sequencing (scRNA-seq) of microglia in mice, a key preclinical model, has shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains (WSB/EiJ, CAST/EiJ, and PWK/PhJ) with and without APP/PS1 demonstrates that genetic diversity significantly alters features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. Results show significant variation in the abundance of microglial subtypes or states, including numbers of previously identified disease-associated and interferon-responding microglia, across the strains. For each subtype, significant differences in the expression of many genes are observed in wild-derived strains relative to B6, including 19 genes previously associated with human AD including Apoe, Trem2, and Sorl1. This resource is critical in the development of appropriately targeted therapeutics for AD and other neurological diseases.
遗传和全基因组关联研究表明，小胶质细胞在阿尔茨海默病（AD）中起核心作用。然而，在关键的临床前模型小鼠中小胶质细胞的单细胞 RNA 测序（scRNA-seq）在向人类研究的转化方面显示出混合的结果。为了解决这个问题，对 C57BL/6J（B6）和野生来源的品系（WSB/EiJ、CAST/EiJ 和 PWK/PhJ）的小胶质细胞进行 scRNA-seq，研究了有无 APP/PS1 的情况下，遗传多样性如何显著改变小胶质细胞在基线神经免疫功能和淀粉样变性反应中的特征和动态。结果表明，在各品系中，小胶质细胞亚型或状态的丰度存在显著差异，包括先前鉴定的与疾病相关和干扰素反应的小胶质细胞的数量。对于每种亚型，与 B6 相比，野生来源的品系中小胶质细胞的许多基因表达存在显著差异，包括 19 个先前与人类 AD 相关的基因，包括 Apoe、Trem2 和 Sorl1。这个资源对于开发针对 AD 和其他神经疾病的靶向治疗方法至关重要。
