Tick tock in the brain: Chinese scientists provide molecular insights into primate hippocampal aging
IMAGE: DANGEROUS PROTEIN AGGREGATES (AMYLOID-BETA) ACCUMULATE IN THE AGED MONKEY HIPPOCAMPUS. view more
CREDIT: GUANGHUI LIU, INSTITUTE OF ZOOLOGY, CHINESE ACADEMY OF SCIENCE
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 Zoology 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 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.
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.
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All relevant data can be accessed via an interactive user-friendly webtool at Aging Atlas.
Reference: Hui Zhang et al (2021). Single-nucleus transcriptomic landscape of primate hippocampal aging, Protein & Cell DOI: 10.1007/s13238-021-00852-9
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Protein & Cell is a peer-reviewed international journal that publishes original research articles, reviews, and commentaries concerning latest development in multidisciplinary areas in biology and biomedicine, with an emphasis on protein and cell research. The subject areas include, but are not limited to biochemistry, biophysics, cell biology, oncology, genetics, immunology, microbiology, molecular biology, neuroscience, stem cell, plant science, protein science, structural biology and translational medicine. In addition, we also address the up-to- date research highlights, news and views, and commentaries covering research policies and funding trends in China. The recent impact factor of Protein & Cell is 10.164.
DOI
10.1007/s13238-021-00852-9
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animal tissue samples
ARTICLE TITLE
Single-nucleus transcriptomic landscape of primate hippocampal aging
ARTICLE PUBLICATION DATE
29-May-2021
Antibodies dovetail with protection, study in non-human primates shows
Peer-Reviewed PublicationA study by Kizzmekia Corbett et al. reports that antibody responses induced by the mRNA-1273 (Moderna) vaccine are a correlate of protection against SARS-CoV-2 infection in non-human primates. Defining immune correlates of protection is a critical aspect of vaccine development for extending the use of approved vaccines and facilitating the development of new candidate vaccines. Although immune responses associated with protection after primary infection have been assessed in non-human primates (NHPs), there are no studies to date that have specifically defined immune correlates of protection in upper and lower airways after vaccination with any COVID-19 vaccine approved for use in humans. To investigate the correlates of protection for such a vaccine, Kizzmekia Corbett et al. studied NHP immune responses to various doses of the mRNA-1273 vaccine. Using bronchoalveolar lavages and nasal washes, they determined that mRNA-1273 vaccination elicited spike protein-specific antibodies in the airways, which correlated with protection against SARS-CoV-2 replication in the lungs. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway, the authors found, which may explain why the current crop of vaccines is more effective against severe lower tract disease. To determine if the antibodies generated from the vaccine are not only a correlate of protection but also the mechanism of protection, the researchers transferred NHP antibodies to Syrian hamsters and found they offered protection against SARS-CoV-2 challenge. The authors note that ongoing NHP studies will assess the durability of mRNA-1273-elicited protection against global SARS-CoV-2 variants.
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JOURNAL
Science
DOI
10.1126/science.abj0299
ARTICLE TITLE
Immune Correlates of Protection by mRNA-1273 against SARS-CoV-2 in Nonhuman Primates
ARTICLE PUBLICATION DATE
29-Jul-2021
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