美国索尔克生物研究所Fred H. Gage和Jerome Mertens研究团队合作取得一项新成果。经过不懈努力，他们的论文发现老年人中有丝分裂后神经元衰老增加是阿尔茨海默病（AD）的病理特征。2022年12月1日出版的《细胞-干细胞》发表了这项成果。

研究人员发现，AD患者大脑中表达衰老标志物的神经元比例明显更高，它们的分布具有旁观者效应。AD患者来源的直接诱导神经元（iN）具有活跃的转录组，表观遗传和分子生物标志物，这表明特定的人类神经元衰老样状态。AD iN单细胞转录组学数据显示，衰老样神经元面临致癌挑战和代谢功能障碍，并具有促炎特征。对AD iN和患者脑脊液的炎症分泌组综合分析揭示了神经元衰老相关的分泌表型，该表型可能在人星形胶质细胞中引发星形胶质细胞病。最后，该研究表明，用衰老治疗剂靶向衰老样神经元可能是预防或治疗AD的一种新策略。

据悉，衰老仅存在于增殖细胞这一概念受到了越来越多的挑战，例如有证据表明终末分化细胞（包括神经元）中同样存在衰老样特征。衰老细胞在生命后期的持续存在与组织功能障碍和年龄相关疾病的风险增加有关。

附：英文原文

Title: Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease

Author: Joseph R. Herdy, Larissa Traxler, Ravi K. Agarwal, Lukas Karbacher, Johannes C.M. Schlachetzki, Lena Boehnke, Dina Zangwill, Doug Galasko, Christopher K. Glass, Jerome Mertens, Fred H. Gage

Issue&Volume: 2022/12/01

Abstract: The concept of senescence as a phenomenon limited to proliferating cells has beenchallenged by growing evidence of senescence-like features in terminally differentiatedcells, including neurons. The persistence of senescent cells late in life is associatedwith tissue dysfunction and increased risk of age-related disease. We found that Alzheimer’sdisease (AD) brains have significantly higher proportions of neurons that expresssenescence markers, and their distribution indicates bystander effects. AD patient-deriveddirectly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecularbiomarker signatures, indicating a specific human neuronal senescence-like state.AD iN single-cell transcriptomics revealed that senescent-like neurons face oncogenicchallenges and metabolic dysfunction as well as display a pro-inflammatory signature.Integrative profiling of the inflammatory secretome of AD iNs and patient cerebralspinal fluid revealed a neuronal senescence-associated secretory phenotype that couldtrigger astrogliosis in human astrocytes. Finally, we show that targeting senescence-likeneurons with senotherapeutics could be a strategy for preventing or treating AD.

DOI: 10.1016/j.stem.2022.11.010

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00457-X