Killing the buzz: NK cells in the aged brain

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Science Immunology  08 Jan 2021:
Vol. 6, Issue 55, eabg3186
DOI: 10.1126/sciimmunol.abg3186


Senescent neuroblasts activate NK cells in the dentate gyrus of the aged brain, leading to neuronal destruction that impairs cognition.

The systemic inflammation associated with aging is known to drive many age-related disorders, but its effect on the brain remains uncharacterized. Jin et al. studied immune cells in human brains and found that older individuals preferentially accumulated NK cells in the dentate gyrus, a part of the hippocampus that is known to generate new neurons throughout life and is critical to the formation of memories and the integration of sensory input. These NK cells expressed activation and cytotoxicity molecules and were found in close proximity to newly formed neurons, termed neuroblasts. Moving to mouse models, the authors found that NK cells accumulated in the dentate gyrus but not in the blood or other organs of aged mice. Single-cell RNA sequencing and fate mapping studies demonstrated that activated, cytotoxic NK cells proliferated locally in the brains of aged but not young mice. Additional studies demonstrated that IL-27 and NK-activating surface receptors produced by senescent neuroblasts were driving NK-mediated destruction of neuroblasts. Depletion of NK cells led to increased numbers of neuroblasts in aged brains and to increased cognitive function in mice tested in a water maze. Taken together, the authors’ studies demonstrate that aged neuroblasts expressing the senescence-associated secretory phenotype (SASP) drive the local accumulation, proliferation, and cytotoxicity of NK cells and that the resulting depletion of neuroblasts has negative impacts on cognition. These studies raise the possibility that senolytic therapies, treatments that deplete senescent cells, may have a role in improving cognition by down-regulating inflammatory neuronal destruction

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