Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street - BRC 1303, Oklahoma City, OK, 731042, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
Geroscience. 2020 Apr;42(2):409-428. doi: 10.1007/s11357-020-00154-8. Epub 2020 Jan 20.
Whole brain irradiation (WBI, also known as whole brain radiation therapy or WBRT) is a mainstream therapy for patients with identifiable brain metastases and as a prophylaxis for microscopic malignancies. WBI accelerates brain aging, causing progressive cognitive dysfunction in ~ 50% of surviving patients, thus compromising quality of life. The mechanisms responsible for this WBI side effect remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that WBI induces astrocyte senescence, which contributes to impaired astrocytic neurovascular coupling (NVC) responses and the genesis of cognitive decline. To achieve this goal, we used transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells. We subjected these mice to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks). WBI-treated and control mice were tested for spatial memory performance (radial arm water maze), astrocyte-dependent NVC responses (whisker-stimulation-induced increases in cerebral blood flow, assessed by laser speckle contrast imaging), NVC-related gene expression, astrocytic release of eicosanoid gliotransmitters and the presence of senescent astrocytes (by flow cytometry, immunohistochemistry and gene expression profiling) at 6 months post-irradiation. WBI induced senescence in astrocytes, which associated with NVC dysfunction and impaired performance on cognitive tasks. To establish a causal relationship between WBI-induced senescence and NVC dysfunction, senescent cells were depleted from WBI-treated animals (at 3 months post-WBI) by genetic (ganciclovir treatment) or pharmacological (treatment with the BCL-2/BCL-xL inhibitor ABT263/Navitoclax, a known senolytic drug) means. In WBI-treated mice, both treatments effectively eliminated senescent astrocytes, rescued NVC responses, and improved cognitive performance. Our findings suggest that the use of senolytic drugs can be a promising strategy for preventing the cognitive impairment associated with WBI.
全脑照射（WBI，也称为全脑放射治疗或 WBRT）是一种针对可识别脑转移瘤患者的主流治疗方法，也是预防微小恶性肿瘤的方法。WBI 加速了大脑衰老，导致约 50%的幸存患者出现进行性认知功能障碍，从而降低了生活质量。导致这种 WBI 副作用的机制仍不清楚，也没有有效的治疗或预防策略。在这里，我们检验了 WBI 诱导星形胶质细胞衰老，从而导致星形胶质细胞神经血管耦联（NVC）反应受损和认知能力下降的假说。为了实现这一目标，我们使用了允许检测和选择性消除衰老细胞的 p16-3MR 转基因小鼠。我们让这些小鼠接受了一个临床相关的分割 WBI 方案（每周两次，每次 5Gy，共 4 周）。在照射后 6 个月，我们用空间记忆表现（放射臂水迷宫）、由激光散斑对比成像评估的星形胶质细胞依赖性 NVC 反应（胡须刺激引起的脑血流增加）、与 NVC 相关的基因表达、星形胶质细胞释放的类花生酸神经递质和衰老星形胶质细胞的存在（通过流式细胞术、免疫组织化学和基因表达谱分析）来测试 WBI 处理和对照组小鼠。WBI 诱导了星形胶质细胞衰老，与 NVC 功能障碍和认知任务表现受损有关。为了确定 WBI 诱导的衰老与 NVC 功能障碍之间的因果关系，我们通过基因（更昔洛韦治疗）或药理学（用 BCL-2/BCL-xL 抑制剂 ABT263/Navitoclax 治疗，这是一种已知的衰老细胞溶解药物）手段从 WBI 处理的动物中去除衰老细胞（在 WBI 后 3 个月）。在 WBI 处理的小鼠中，两种处理方法都能有效地消除衰老的星形胶质细胞，恢复 NVC 反应，并改善认知表现。我们的研究结果表明，使用衰老细胞溶解药物可能是预防 WBI 相关认知障碍的一种有前途的策略。
