美国哈佛医学院Sudeshna Das研究组揭示阿尔茨海默病时空进程中星形胶质细胞转录组变化。2024年11月11日，《自然—神经科学》杂志在线发表了这项成果。

研究人员对来自32位捐赠者的五个大脑区域中628943个星形胶质细胞进行了单核RNA测序，涵盖了从正常衰老到严重阿尔茨海默病（AD）的整个谱系，代表了AD病理学的典型进展。研究人员绘制了多个独特的星形胶质细胞亚群，这些亚群在AD易感神经网络（空间轴）或AD病理阶段（时间轴）上表现出不同的响应。

稳态型、中间型和反应型星形胶质细胞的比例仅在空间轴上发生变化，而另外两个亚群则沿时间轴发生变化。其中，一个富含滋养因子的亚群在病理进展过程中下降。而另一个在晚期增加，但在终末期恢复到基线水平，提示在长期暴露于神经病理学的情况下，星形胶质细胞的反应可能已被耗竭。该研究强调了星形胶质细胞在AD中的复杂动态反应。

研究人员表示，星形胶质细胞对大脑稳态至关重要，但它们在AD神经病理学时空进程中的变化仍未被深入探讨。

附：英文原文

Title: Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Author: Serrano-Pozo, Alberto, Li, Huan, Li, Zhaozhi, Muoz-Castro, Clara, Jaisa-aad, Methasit, Healey, Molly A., Welikovitch, Lindsay A., Jayakumar, Rojashree, Bryant, Annie G., Noori, Ayush, Connors, Theresa R., Hu, Miwei, Zhao, Karen, Liao, Fan, Lin, Gen, Pastika, Timothy, Tamm, Joseph, Abdourahman, Aicha, Kwon, Taekyung, Bennett, Rachel E., Woodbury, Maya E., Wachter, Astrid, Talanian, Robert V., Biber, Knut, Karran, Eric H., Hyman, Bradley T., Das, Sudeshna

Issue&Volume: 2024-11-11

Abstract: Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer’s disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate and reactive astrocytes changed only along the spatial axis, whereas two other subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stages, whereas the other increased in the late stage but returned to baseline levels in the end stage, suggesting an exhausted response with chronic exposure to neuropathology. Our study underscores the complex dynamics of astrocytic responses in AD.

DOI: 10.1038/s41593-024-01791-4

Source: https://www.nature.com/articles/s41593-024-01791-4