美国华盛顿大学医学院Marco Colonna和Maxim N. Artyomov研究组合作发现，人和小鼠单核转录组学揭示了阿尔茨海默病（AD）中髓样细胞2（TREM2）依赖和TREM2不依赖的细胞反应。这一研究成果在线发表在2020年1月13日的国际学术期刊《自然—医学》上。

通过单核RNA测序，课题组研究了5XFAD小鼠和人AD中与AD病理和TREM2相关的基因表达变化。他们确定存在Trem2依赖性疾病相关小胶质细胞（DAM），并鉴定了小鼠中以前未发现的Serpina3n+C4b+反应性少突胶质细胞群。有趣的是，在人类AD中存在明显不同的神经胶质表型。小胶质细胞信号使人联想到IRF8驱动的反应性小胶质细胞在周围神经损伤中的作用。少突胶质细胞信号提示轴突髓鞘受损和对神经元退化的代谢适应。星形胶质细胞特征表明与神经元的代谢协调减弱。值得注意的是，尽管没有明显的物种特异性差异，TREM2-R47H和TREM2-R62H携带者的小胶质细胞反应表型不如非携带者，这表明小鼠和人类AD都需要TREM2。

据悉，胶质细胞与AD发病机理有关。在TREM2上表达的小胶质细胞触发受体的变体增加了AD的风险，DAM的激活取决于AD小鼠模型中的TREM2。

附：英文原文

Title: Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease

Author: Yingyue Zhou, Wilbur M. Song, Prabhakar S. Andhey, Amanda Swain, Tyler Levy, Kelly R. Miller, Pietro L. Poliani, Manuela Cominelli, Shikha Grover, Susan Gilfillan, Marina Cella, Tyler K. Ulland, Konstantin Zaitsev, Akinori Miyashita, Takeshi Ikeuchi, Makoto Sainouchi, Akiyoshi Kakita, David A. Bennett, Julie A. Schneider, Michael R. Nichols, Sean A. Beausoleil, Jason D. Ulrich, David M. Holtzman, Maxim N. Artyomov, Marco Colonna

Issue&Volume: 2020/01/13

Abstract: Glia have been implicated in Alzheimers disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences. Single-nucleus RNA sequencing in a mouse model of A accumulation and postmortem brain tissue from people with Alzheimers disease reveals substantial species-specific differences in transcriptional signatures, but both point to the contribution of glia and the importance of TREM2.

DOI: 10.1038/s41591-019-0695-9

Source: https://www.nature.com/articles/s41591-019-0695-9