China National Clinical Research Center for Neurological Diseases, Jing-Jin Center for Neuroinflammation, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Nat Neurosci. 2021 Jan;24(1):61-73. doi: 10.1038/s41593-020-00745-w. Epub 2020 Nov 30.
Normal aging is accompanied by escalating systemic inflammation. Yet the potential impact of immune homeostasis on neurogenesis and cognitive decline during brain aging have not been previously addressed. Here we report that natural killer (NK) cells of the innate immune system reside in the dentate gyrus neurogenic niche of aged brains in humans and mice. In situ expansion of these cells contributes to their abundance, which dramatically exceeds that of other immune subsets. Neuroblasts within the aged dentate gyrus display a senescence-associated secretory phenotype and reinforce NK cell activities and surveillance functions, which result in NK cell elimination of aged neuroblasts. Genetic or antibody-mediated depletion of NK cells leads to sustained improvements in neurogenesis and cognitive function during normal aging. These results demonstrate that NK cell accumulation in the aging brain impairs neurogenesis, which may serve as a therapeutic target to improve cognition in the aged population.
正常衰老伴随着不断加剧的系统性炎症。然而,免疫稳态对大脑衰老过程中神经发生和认知能力下降的潜在影响尚未得到解决。在这里,我们报告说,先天免疫系统的自然杀伤 (NK) 细胞存在于人类和小鼠衰老大脑的齿状回神经发生龛位中。这些细胞的原位扩增有助于增加其数量,其数量远远超过其他免疫亚群。衰老齿状回内的神经前体细胞表现出与衰老相关的分泌表型,并增强 NK 细胞的活性和监视功能,导致 NK 细胞清除衰老的神经前体细胞。NK 细胞的基因或抗体耗竭会导致正常衰老过程中神经发生和认知功能的持续改善。这些结果表明,衰老大脑中 NK 细胞的积累会损害神经发生,这可能成为改善老年人群认知能力的治疗靶点。
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