Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.
Nat Commun. 2021 May 21;12(1):3015. doi: 10.1038/s41467-021-23111-1.
The role of microglia cells in Alzheimer's disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4) and non-containing (XO4) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4 microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4 microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4 microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4 microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.
小胶质细胞在阿尔茨海默病（AD）中的作用已得到充分认识，但它们的分子和功能多样性仍不清楚。在这里，我们从小鼠 AD 模型中分离出含有淀粉样斑块（使用 methoxy-XO4 标记，XO4）和不含有淀粉样斑块（XO4）的小胶质细胞。转录组学分析确定了衰老和 AD 小鼠中不同的转录轨迹。XO4 小胶质细胞转录组显示与晚发性 AD 相关的基因表达失调。我们进一步表明，从 AD 患者大脑中分离出的人类小胶质细胞的一部分存在与来自小鼠的 XO4 小胶质细胞相关的转录程序。与 XO4 小胶质细胞相比，XO4 小胶质细胞表现出与加速衰老相关的转录特征，并且含有更多的细胞内突触后物质，尽管其活性突触吞噬作用减少。我们使用原代人小胶质细胞和 BV2 小鼠小胶质细胞鉴定出 HIF1α 可能在体外调节突触吞噬作用。综上所述，这些发现为 AD 中小胶质细胞功能多样性的分子机制提供了深入了解。
