许多癌症患者经历与治疗相关的严重认知问题，这会极大地影响他们的生活质量。这种癌症化疗引起的认知障碍（CICI）的分子机制尚不清楚，因此减缓了预防方法的发展。我们假设癌症化疗可能会诱导大脑细胞衰老，创造促炎环境并破坏正常的大脑通讯。我们使用常见的化疗药物阿霉素在两个独立的小鼠模型中测试了这一假设。在第一个模型中，我们使用在 pdkn2a (p16) 启动子下表达 tdTomato 的小鼠； p16 是细胞衰老的调节因子，其上调由荧光标记细胞的存在来表示。暴露于三剂5mg/kg阿霉素两周后，大脑皮层和海马中tdTomato阳性细胞的数量增加了近三倍。 td番茄染色与神经元、小胶质细胞、少突胶质细胞前体细胞和内皮细胞共定位，但不与星形胶质细胞共定位。在第二个模型中，我们使用 APOE 敲入小鼠，因为 APOE4 等位基因是人类和小鼠模型中 CICI 的危险因素。我们从单剂量 10mg/kg 阿霉素后 1 至 21 天的 APOE3 和 APOE4 小鼠的大脑皮层中分离了 RNA。通过对 700 多个与神经炎症相关的基因进行 NanoString 分析以及对大脑皮层转录本进行 RT-qPCR 分析，我们发现与 APOE3 对照小鼠相比，APOE4 小鼠在三周时四个衰老相关基因的诱导增加了两倍：p21(cdkn1a) 、p16、Gadd45a 和 Egr1。我们得出结论，阿霉素可促进大脑中的细胞衰老途径，支持消除衰老细胞的药物可用于预防 CICI 的假设。版权所有 © 2023。由 Elsevier Inc. 出版。

Many cancer patients experience serious cognitive problems related to their treatment, which can greatly affect their quality of life. The molecular mechanisms of this cancer chemotherapy-induced cognitive impairment (CICI) are unknown, thus slowing the development of preventative approaches. We hypothesized that cancer chemotherapies could induce cellular senescence in the brain, creating a pro-inflammatory environment and damaging normal brain communication. We tested this hypothesis using the common chemotherapeutic agent doxorubicin in two independent mouse models. In the first model, we used mice that express tdTomato under the pdkn2a (p16) promoter; p16 is a regulator of cellular senescence, and its upregulation is denoted by the presence of fluorescently tagged cells. Two weeks after exposure to three doses of 5 mg/kg doxorubicin, the number of tdTomato positive cells were increased nearly three-fold in both the cerebral cortex and the hippocampus. tdTomato staining co-localized with neurons, microglia, oligodendrocyte precursor cells, and endothelial cells, but not astrocytes. In the second model, we used APOE knock-in mice, since the APOE4 allele is a risk factor for CICI in humans and mouse models. We isolated RNA from the cerebral cortex of APOE3 and APOE4 mice from one to 21 days after a single dose of 10 mg/kg doxorubicin. Using NanoString analysis of over 700 genes related to neuroinflammation and RT-qPCR analysis of cerebral cortex transcripts, we found two-fold induction of four senescence-related genes at three weeks in the APOE4 mice compared to the APOE3 control mice: p21(cdkn1a), p16, Gadd45a, and Egr1. We conclude that doxorubicin promotes cellular senescence pathways in the brain, supporting the hypothesis that drugs to eliminate senescent cells could be useful in preventing CICI.Copyright © 2023. Published by Elsevier Inc.