Chia Sook-Yoong, Li Mengwei, Li Zhihong, Tu Haitao, Lee Jolene Wei Ling, Qiu Lifeng, Ling Jingjing, Reynolds Richard, Albani Salvatore, Tan Eng-King, Ng Adeline Su Lyn, Chen Jinmiao, Zeng Li
Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore, 308433, Singapore.
Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, 138673, Singapore.
Genome Med. 2025 Aug 18;17(1):92. doi: 10.1186/s13073-025-01519-4.
Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD) collectively represent the majority of dementia cases worldwide. While these subtypes share clinical, genetic, and pathological features, their transcriptomic similarities and differences remain poorly understood.
We applied single-nucleus RNA-sequencing (snRNA-seq) to prefrontal cortex samples from individuals with non-cognitive impairment control (NCI), and dementia subtypes (AD, DLB, and PDD) to investigate cell type-specific gene expression patterns and pathways underlying pathological similarities and differences across dementia subtypes. SnRNA-seq findings were validated through RNAscope, immunohistochemistry, and additional biochemical analyses in human tissues and cellular models.
SnRNA-seq analysis revealed elevated microglial proportions across all dementia subtypes compared to NCI. Further analysis of cell type-specific transcriptomes identified overlapping differentially expressed genes (DEGs) between microglia and oligodendrocytes across all dementia subtypes. While AD showed molecular similarities to NCI, PDD and DLB were clustered more closely together, sharing a greater number of DEGs and related pathways, predominantly associated with microglia. Investigation of interactions between microglia and oligodendrocytes revealed a distinct microglial state in all dementia subtypes. MSR1, a gene encoding a scavenger receptor, was upregulated in microglia across all dementia subtypes, along with its associated gene HSPA1A in oligodendrocytes. RNAscope supported the potential interaction between microglia and oligodendrocytes, where these cells were in closer proximity to each other in human cortical tissues of PDD compared to NCI. MSR1 expression was significantly increased in cortical primary microglia from PD mice compared with non-transgenic (NTg) mice. Additionally, the expression of myelin-associated genes (MBP, MOBP, and PLP1) was significantly upregulated in PD microglia compared to NTg, supporting the presence of the distinct microglia. Furthermore, MSR1-positive microglia colocalised with MBP in cortical tissue of PDD patients, suggesting a functional role of MSR1 in myelin debris clearance. Overexpression of MSR1 in microglial cells enhanced their phagocytic activity toward myelin, and reciprocally, myelin treatment upregulated MSR1 protein levels, indicating enhanced MSR1-mediated myelin phagocytosis.
Our findings provide novel insights into the cell type-specific role of microglial MSR1 in AD, DLB, and PDD, linking its increased phagocytic capacity to myelin defects as a common feature of neurodegenerative dementias.
阿尔茨海默病（AD）、路易体痴呆（DLB）和帕金森病痴呆（PDD）共同构成了全球大多数痴呆病例。虽然这些亚型具有临床、遗传和病理特征，但它们在转录组水平上的异同仍知之甚少。
我们对非认知功能障碍对照（NCI）个体以及痴呆亚型（AD、DLB和PDD）个体的前额叶皮质样本进行了单核RNA测序（snRNA-seq），以研究细胞类型特异性基因表达模式以及痴呆亚型间病理异同背后的通路。通过RNAscope、免疫组织化学以及在人体组织和细胞模型中的其他生化分析对snRNA-seq结果进行了验证。
snRNA-seq分析显示，与NCI相比，所有痴呆亚型中的小胶质细胞比例均升高。对细胞类型特异性转录组的进一步分析确定了所有痴呆亚型中小胶质细胞和少突胶质细胞之间重叠的差异表达基因（DEG）。虽然AD在分子水平上与NCI相似，但PDD和DLB聚类更为紧密，共享更多的DEG和相关通路，主要与小胶质细胞有关。对小胶质细胞和少突胶质细胞之间相互作用的研究揭示了所有痴呆亚型中一种独特的小胶质细胞状态。MSR1是一种编码清道夫受体的基因，在所有痴呆亚型的小胶质细胞中均上调，其在少突胶质细胞中的相关基因HSPA1A也上调。RNAscope支持小胶质细胞和少突胶质细胞之间的潜在相互作用，与NCI相比，在PDD的人体皮质组织中这些细胞彼此更接近。与非转基因（NTg）小鼠相比，PD小鼠皮质原代小胶质细胞中MSR1表达显著增加。此外，与NTg相比，PD小胶质细胞中髓鞘相关基因（MBP、MOBP和PLP1）的表达显著上调支持了独特小胶质细胞的存在。此外，PDD患者皮质组织中MSR1阳性小胶质细胞与MBP共定位，表明MSR1在髓鞘碎片清除中具有功能作用。小胶质细胞中MSR1的过表达增强了它们对髓鞘的吞噬活性，反之，髓鞘处理上调了MSR1蛋白水平，表明MSR1介导的髓鞘吞噬作用增强。
我们的研究结果为小胶质细胞MSR1在AD、DLB和PDD中的细胞类型特异性作用提供了新见解，将其吞噬能力的增强与髓鞘缺陷联系起来，这是神经退行性痴呆的一个共同特征。
