Zemke Nathan R, Lee Seoyeon, Mamde Sainath, Yang Bing, Berchtold Nicole, Maximiliano Garduño B, Indralingam Hannah S, Bartosik Weronika M, Lau Pik Ki, Dong Keyi, Yang Amanda, Tani Yasmine, Chen Chumo, Zeng Qiurui, Ajith Varun, Tong Liqi, Seng Chanrung, Li Daofeng, Wang Ting, Xu Xiangmin, Ren Bing
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine; La Jolla, CA, USA.
Center for Epigenomics, University of California, San Diego School of Medicine; La Jolla, CA, USA.
bioRxiv. 2024 Oct 17:2024.10.14.618338. doi: 10.1101/2024.10.14.618338.
Age-related cognitive decline is associated with altered physiology of the hippocampus. While changes in gene expression have been observed in aging brain, the regulatory mechanisms underlying these changes remain underexplored. We generated single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D genome data from 40 human hippocampal tissues spanning adult lifespan. We observed a striking loss of astrocytes, OPC, and endothelial cells during aging, including astrocytes that play a role in regulating synapses. Microglia undergo a dramatic switch from a homeostatic state to a primed inflammatory state through DNA methylome and 3D genome reprogramming. Aged cells experience erosion of their 3D genome architecture. Our study identifies age-associated changes in cell types/states and gene regulatory features that provide insight into cognitive decline during human aging.
与年龄相关的认知衰退与海马体生理变化有关。虽然在衰老大脑中已观察到基因表达的变化，但这些变化背后的调控机制仍未得到充分探索。我们从40个人类海马体组织中生成了跨越成年期寿命的单核基因表达、染色质可及性、DNA甲基化和三维基因组数据。我们观察到衰老过程中星形胶质细胞、少突胶质前体细胞和内皮细胞显著减少，包括在调节突触中起作用的星形胶质细胞。小胶质细胞通过DNA甲基化组和三维基因组重编程从稳态急剧转变为预激炎症状态。衰老细胞经历三维基因组结构的侵蚀。我们的研究确定了与年龄相关的细胞类型/状态变化和基因调控特征，为人类衰老过程中的认知衰退提供了见解。
