Post by Flora Moujaes
What's the science?
The deterioration of tissues in the body, including brain tissue, is a hallmark of aging. But what are the mechanisms underlying this deterioration? Answering this question could help develop treatments for preventing aging. The brain contains neural stem cells that are responsible for the formation of new neurons in the brain. This process, known as neurogenesis, decreases with age. We still don’t fully understand why old age leads to a decrease in neurogenesis. The intrinsic properties of young and old neural stem cells are the same, therefore the reduced functioning of neural stem cells in older brains may be due to changes in their environment rather than the cells themselves. Neural stem cells can be located in a specialized microenvironment in the brain called a niche, which includes a number of other molecules and cells that support the stem cells’ ability to function. This week in Nature, Dulken and colleagues investigate how aging affects the neural stem cell niche in mice, and show for the first time that there is an infiltration of T-cells (immune cells not normally found in the brain) in the neural stem cell niche of older mice.
How did they do it?
First, to examine whether changes in the environment of neural stem cells are related to the reduction in neurogenesis in older mammals, the authors examined gene expression in individual cells found in the neural stem cell niche of the mouse brain. They compared three 3-month-old and three 28-month old mice, analysing the activation levels of the genes in nearly 15,000 cells. The researchers focused on cells in a specific region known as the subventricular zone, one of two places where neurogenesis has been found to occur in the adult mammalian brain. They used single-cell RNA sequencing to analyse the transcriptomes of each cell. The transcriptome or messenger RNA is essentially DNA in action: it is a set of molecules copied from DNA sequences that tell the cell how to behave.
Second, to explore the hypothesis that the T cells decrease the proliferation of neural stem cells, the researchers also examined what happened when (i) they enabled T cells to enter the brains of young mice and (ii) they cultured neural stem cells from young mice in vitro (i.e. in a petri dish) either in the presence or absence of T cells.
Finally, in order to determine whether their findings were generalizable from mice to humans, they also conducted an experiment on post-mortem human brain tissue, testing for the presence of T cells.
What did they find?
The authors identified eleven different cell types in the neural stem cell niche of the adult mouse brain and found that as expected, there were major differences in transcription between the young and old mice, as well as a 75% reduction in the number of neural stem cells. However, they also identified a large number of T cells (immune cells not usually found in the brain) in older mice. Furthermore, these T cells were located in close proximity to the neural stem cells. The T cells also differed from those usually found in blood, as the T cells in the brains of older mice secreted high levels of the molecule interferon-γ. Neural stem cells have receptors for a signalling interferon-γ, which discourages them from performing their normal function, and the researchers suggest that this is likely to be the main reason why neural stem cells may fail to replicate at the same rate in aged brains.
The authors enabled T cells to enter the brains of young mice and cultured neural stem cells from these young mice in vitro in the presence or absence of T-cells. In both cases, the presence of T cells resulted in a reduction in neurogenesis. Furthermore, they found that introducing an antibody to interferon-γ was able to restore this neurogenesis.
Finally, to determine whether these results could be generalized to humans, the authors examined post-mortem human brain tissue for the presence of T cells. T cells were present in the lining of the lateral ventricles and were more abundant in people aged 79-93 compared to people aged 20-44. This suggests that a similar mechanism could suppress neurogenesis in mice and humans.
What's the impact?
This is the first study to show that T-cells infiltrate the brain of older mice and that their expression of interferon-γ may explain decreased neurogenesis in aging brains. The authors note that T cells in the aging brain appear to have proliferated through clonal expansion: an immune response to an antigen or harmful molecule wherein cells reproduce rapidly in order to protect the body. Another possibility is that T cells are merely able to enter the brain due to age-related disruptions in the blood-brain barrier. Overall these results may help us to better understand why brain function deteriorates with age, and opens new possibilities for finding treatments to ameliorate brain deterioration.
Dulken et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature (2019). Access the original scientific publication here.