Loss of Neurogenesis with Age is in Part Mediated by Inflammatory Signaling in the Brain

The immune system is intimately involved in tissue function throughout the body, but particularly so in the brain. The immune system of the brain is distinct from that of the rest of the body, the two separated by the blood-brain barrier, and the immune cells of the brain participate in a range of activities necessary to the function of neurons, as well as the creation, destruction, and maintenance of synaptic connections between neurons. It isn't surprising to find links between immune aging, inflammatory signaling, and dysfunction of many systems in the brain. The focus in the commentary noted here is on age-related loss of neurogenesis, the creation of new neurons from neural stem cells, followed by their integration into existing neural circuits. Immune cells contribute to this loss of neural stem cell activity via their inflammatory signaling.

Why neurogenesis is attenuated in elderly individuals is an intriguing question that has raised renewed interest. Mechanisms associated with declined neurogenesis in the aged brain have been attributed to inflammatory cytokines. More recently, a specific role for interferon-γ (IFN-γ) produced by CD8-expressing cytotoxic T cells has been implicated. These observations suggest a scenario in which neurogenesis, at least in part, is regulated by immune cells within the aging brain. This raises several interesting questions with regards to the characteristics of specific immune cells within the brain, the signals for their expansion and maintenance, and their role in affecting neurogenesis and cognition during normal brain aging.

Further detailed insights into these processes have now been provided. In a recently published study, researchers analyzed the subtypes, frequencies, and location of immune cells in young and aged brains. Strikingly, an abundant population of natural killer (NK) cells in the dentate gyrus of brains from old humans was observed. NK cells are innate lymphocytes, with some adaptive features, that normally play a critical role in fighting virus infections and tumors. These NK cells outnumbered neutrophils, monocytes, and adaptive T lymphocytes and B lymphocytes in the brain, and were characterized by the expression of specific activation and cytotoxicity markers. These and other observations led the authors to conclude that NK cells may accumulate in specific regions of the human brain with age, in particular in the dentate gyrus. Similar observations were made in mouse studies.

It was found that the NK cell chemokine CCL3 and the growth factors GM-CSF, IL-2 and, particularly, IL-27 were produced in relatively high amounts in the interstitial fluid of the aged dentate gyrus. In studies determining whether IL-27 derived from aged neuroblasts was necessary for local expansion and accumulation of NK cells in the aged dentate gyrus, it was observed that an IL-27-neutralizing antibody blocked these effects. Together, these and other results suggested that neuroblasts sustain NK cells and augment their cytotoxicity in the aged dentate gyrus mediated, at least in part, via IL-27.

In summary, in the brain, NK cells increase with age. They predominantly reside in the dentate gyrus, a neurogenic niche where neuroblasts are also found. As the brain ages, neuroblasts undergo cellular senescence, start to express RAE-1, and produce high levels of IL-27 that induces expansion of NK cells. Notably, RAE-1 is a ligand for the NK cell activation receptor NKG2D. These age-related alterations trigger cytotoxic activity by the NK cells leading to loss of neuroblasts, concomitantly preventing regeneration of neurons resulting in cognitive decline.

Link: https://doi.org/10.1007/s12264-021-00654-3

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