A Hostile Environment for Neurogenesis in the Aging Hippocampus

Neurogenesis, the creation of new neurons and subsequent integration into neural circuits, is necessary for maintenance and function of the brain, particularly in connection to memory. Unfortunately, neurogenesis declines with age. Here, researchers add to the existing body of evidence for chronic inflammation in the brain to contribute to this decline. Unresolved inflammation is considered to contribute to neurodegeneration in general, not just loss of neurogenesis. Finding ways to safely suppress excessive inflammation in the aging body and brain is a high priority in the treatment of aging as a medical condition.

Using brain tissues from non-human primates (NHPs), the ideal model to mimic human hippocampal aging, scientists have established the first single-nucleus transcriptomic landscape of primate hippocampal aging. 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. It 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 helps 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.

Link: https://www.eurekalert.org/news-releases/955145

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