Jiaming Li
Jie Ren
Shuhui Sun
Shuai Ma
Weiqi Zhang
Yang Yu
Yusheng Cai
Kaowen Yan
Wei Li
Baoyang Hu
Piu Chan
Guo-Guang Zhao
Juan Carlos Izpisua Belmonte
Qi Zhou
Jing Qu
Si Wang
Guang-Hui Liu
1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
2 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
3 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China;
4 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
5 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China;
6 University of Chinese Academy of Sciences, Beijing 100049, China;
7 China National Center for Bioinformation, Beijing 100101, China;
8 Aging Translational Medicine Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China;
9 Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China;
10 Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China;
11 Sino-Danish Center for Education and Research, Beijing 101408, China;
12 Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing 100191, China;
13 Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China;
14 Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China;
15 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
Funds: We thank Shanshan Che, Liyun Zhao, Xiaoyan Sun, and Yixin Zhang for their help in immunofluorescence staining, Ruotong Ren, Liping Deng and Xiaojuan He for their help in tissue collection, Junying Jia from the Institute of Biophysics, Chinese Academy of Sciences for his help in fluorescence-activated cell sorting (FACS), as well as Shiwen Li from the Institute of Zoology, Chinese Academy of Sciences for her help in image scanning of immunohistochemical staining. We thank Profs. Fuchou Tang, Xiaoqun Wang, Young Shen, Moshi Song, Fudong Shi and Junying Yuan for their helpful suggestions and discussions. We are grateful to Lei Bai, Qun Chu, Xiao Zhuo, Jing Lu, Ying Yang, Ruijun Bai, and Shikun Ma for administrative assistance. This work was supported by the National Key Research and Development Program of China (2020YFA0804000), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010000), the National Key Research and Development Program of China (2019YFA0110100, 2020YFA0112201, 2018YFC2000100, 2017YFA0103304, 2017YFA0102802, 2018Y FA0107203, 2020YFA0803401, and 2019YFA0802202), the National Natural Science Foundation of China (Grant Nos. 81921006, 81625009, 91749202, 81861168034, 91949209, 92049304, 81822018, 82071588, 92049116, 31900523, 32000500, 31970597, 82030037, and 81801534), the Program of the Beijing Municipal Science and Technology Commission (Z191100001519005), Beijing Natural Science Foundation (Z190019), the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-221), K. C. Wong Education Foundation (GJTD-2019-06, GJTD-2019-08), the International Partnership Program of Chinese Academy of Sciences (152111KYSB20160004), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-JKCS-011), the State Key Laboratory of Stem Cell and Reproductive Biology, the State Key Laboratory of Membrane Biology, the Milky Way Research Foundation (MWRF), and the Moxie Foundation (for J.C.I.B.).
Received Date: 2020-10-07
Accepted Date:2020-11-13
Abstract
Abstract
The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealedimpairedTAPCdivisionandcompromisedneuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.Keywords: aging,
hippocampus,
primate,
single-cell RNA sequencing
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