Deep inside our brain is a region called the hippocampus. It plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. But what drives it down the path of aging?

The hippocampus is a complex structure with a highly heterogeneous cell composition, so it is difficult to accurately reveal the molecular regulatory networks of various cell types contributing to the aging process with traditional techniques. In addition, due to the ethical restrictions, it is difficult to obtain disease-free human brain tissues of both young and old ages. All these factors limited our understanding of the aging mechanism in the human hippocampus, let alone the development of therapeutic interventions.

Using brain tissues from non-human primates (NHPs), the ideal model to mimic human hippocampal aging, scientists from the Institute of Stem Cell and Regeneration of the Chinese Academy of Sciences and Xuanwu Hospital Capital Medical University have worked jointly and established the first single-nucleus transcriptomic landscape of primate hippocampal aging, revealed the molecular mechanism of its functional deterioration with age, and provided a valuable resource for the identification of new diagnostic biomarkers and potential therapeutic targets for interventions against hippocampal aging and related human neurodegenerative disorders. This study entitled “Single-nucleus transcriptomic landscape of primate hippocampal aging” is published online in Protein & Cell on May 30, 2021.

In this study, the aged NHP hippocampus was found to demonstrate an array of aging-associated damages, including genomic and epigenomic instability, loss of proteostasis, as well as increased inflammation. To explore unique cellular and molecular characteristics underlying these age-related phenotypes, scientists generated a high-resolution single-nucleus transcriptomic landscape of hippocampal aging in NHPs. This landscape is composed of the gene expression profiles of 12 major hippocampal cell types, including neural stem cells, transient amplified progenitor cells (TAPC), immature neurons, excitatory/inhibitory neurons, oligodendrocytes, and microglia. Among them, TAPC and microglia were most affected by aging, as they manifested the most aging-related differentially expressed genes and those annotated as high-risk genes for neurodegenerative diseases. In-depth analysis of the dynamic gene-expression signatures of the stepwise neurogenesis trajectory revealed the impaired TAPC division and compromised neuronal function, underlying the early onset and later stage of dysregulation in adult hippocampal neurogenesis, respectively. This landscape also enabled us to to unveil contributing factors to a hostile microenvironment for neurogenesis in the aged hippocampus, namely the elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells. This may aggravate the loss of neurogenesis in the aged hippocampus, and may lead to the further decline of cognitive function and the occurrence of neurodegenerative diseases.

Dangerous protein aggregates (Amyloid-beta) accumulate in the aged monkey hippocampus.

This study established, for the first time, a comprehensive single-nucleus transcriptomic atlas of primate hippocampal aging, which provides extensive resources for the illustration of age-related molecular signatures at the single-cell level, including changes of internal factors and external microenvironment that contribute collectively to the impaired ability for neuronal regeneration in the old hippocampus. It has deepened our understanding of age-related changes in hippocampal structure and function, and identified cell types and molecules that are most susceptible in the aging process of hippocampus, thus enabling the identification of potential diagnostic biomarkers and therapeutic targets for neurodegenerative diseases associated with hippocampal aging.

All relevant data can be accessed via an interactive user-friendly webtool at Aging Atlas (https://bigd.big.ac.cn/aging/index).

This collaborative work was conducted by the Institute of Zoology of the Chinese Academy of Sciences (CAS), the National Clinical Research Center for Geriatric disorders in Xuanwu Hospital Capital Medical University, the Institute of Stem Cell and Regeneration of CAS, Beijing Institute of Genomics of CAS, Peking University Third Hospital, Beijing Institute for Stem Cell and Regenerative Medicine. Hui Zhang, a doctoral candidate at the Institute of Zoology of CAS, Jiaming Li, a graduate student at the Beijing Institute of Genomics of CAS, and Jie Ren, a PI at the Beijing Institute of Genomics of CAS / China national center for bioinformation are the co-first authors. Guang-Hui Liu, a PI at the Institute of Zoology of CAS, Si Wang, a PI at Xuanwu Hospital Capital Medical University, and Jing Qu, a PI at the Institute of Zoology of CAS are the co-corresponding authors. Academician Qi Zhou, Baoyang Hu, and Wei Li, PIs at the Institute of Zoology of CAS, Weiqi Zhang, a PI at the Beijing Institute of Genomics of CAS / China National Center for Bioinformation, Professor Guo-Guang Zhao and Professor Piu Chan from Xuanwu Hospital, and Yang Yu, a PI at Peking University Third Hospital provided important collaboration and support. This work was supported by programs from the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences and Beijing.

Article Link: https://link.springer.com/article/10.1007/s13238-021-00852-9

(Contact: Guang-Hui Liu, ghliu@ioz.ac.cn)