华盛顿大学医学院Erik S. Musiek研究小组报道了神经胶质昼夜节律基因表达图谱揭示了淀粉样蛋白病理或衰老反应中细胞类型和疾病特异性重编程。相关论文于2025年10月23日发表在《自然—神经科学》杂志上。

在这里，研究团队进行了翻译核糖体亲和纯化，以鉴定健康motheme皮层中星形胶质细胞、小胶质细胞和大块组织的昼夜节律翻译体，以及淀粉样蛋白斑块病理或衰老的设置。课题组人员发现，神经胶质昼夜节律翻译体是高度细胞类型特异性的，在淀粉样蛋白病理或衰老反应中表现出深刻的、情境依赖性的重编程。涉及神经胶质反应性、免疫代谢和蛋白质平衡的转录本，以及近一半的阿尔茨海默病风险基因，显示出昼夜节律振荡，其中许多被病理改变。小胶质细胞氧化应激和淀粉样蛋白吞噬在基因表达和功能上表现出时间差异。因此，基因表达的昼夜节律依赖于细胞和环境，并为健康、阿尔茨海默病和衰老中的神经胶质功能提供了重要见解。

据悉，虽然昼夜节律紊乱可能促进神经退行性疾病，但衰老和神经退行性病理对不同脑细胞类型的昼夜节律基因表达模式的影响尚不清楚。

附：英文原文

Title: A glial circadian gene expression atlas reveals cell-type and disease-specific reprogramming in response to amyloid pathology or aging

Author: Sheehan, Patrick W., Fass, Stuart B., Sapkota, Darshan, Kang, Sylvia, Hollis, Henry C., Lawrence, Jennifer H., Park, Sohui, Sharma, Ashish, Schafer, Dorothy P., Anafi, Ron C., Dougherty, Joseph D., Fryer, John D., Musiek, Erik S.

Issue&Volume: 2025-10-23

Abstract: While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer’s disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer’s disease and aging.

DOI: 10.1038/s41593-025-02067-1

Source: https://www.nature.com/articles/s41593-025-02067-1