In the brain, environmental changes, such as neuroinflammation, can induce senescence, characterized by the decreased proliferation of neurons and dendrites and synaptic and vascular damage, resulting in cognitive decline. Senescence promotes neuroinflammatory disorders by senescence-associated secretory phenotypes and ROS. In human brain microvascular endothelial cells (HBMVECs), we demonstrate that chronological aging and irradiation increase death-associated protein kinase 3 (DAPK3) expression. To confirm the role of DAPK3 in HBMVEC senescence, we disrupted DAPK3 activity using small interfering RNA (siRNA) or a dominant-negative mutant (DAPK3-P216S), which reduced cellular senescence phenotypes, as assessed by changes in tube formation, senescence-associated beta-galactosidase activity, and cell proliferation. In endothelial cells, DAPK3 promotes cellular senescence by regulating the phosphorylation and inactivation of peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PGC1α) via the protein kinase B pathway, resulting in the decreased expression of mitochondrial metabolism–associated genes, such as ATP5G1, BDNF, and COX5A. Our studies show that DAPK3 is involved in cellular senescence and PGC1α regulation, suggesting that DAPK3 regulation may be important for treating aging-related brain diseases or the response to radiation therapy.

中文翻译：

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抑制 DAPK3 通过激活脑内皮细胞中 PGC1α 依赖性代谢途径来抑制辐射诱导的细胞衰老

在大脑中，神经炎症等环境变化会引起衰老，其特征是神经元和树突增殖减少以及突触和血管损伤，从而导致认知能力下降。衰老通过衰老相关的分泌表型和 ROS 促进神经炎症性疾病。在人脑微血管内皮细胞 (HBMVEC) 中，我们证明，时间老化和辐射会增加死亡相关蛋白激酶 3 (DAPK3) 的表达。为了证实 DAPK3 在 HBMVEC 衰老中的作用，我们使用小干扰 RNA (siRNA) 或显性失活突变体 (DAPK3-P216S) 破坏 DAPK3 活性，通过管形成、衰老相关的变化来评估，这减少了细胞衰老表型。 β-半乳糖苷酶活性和细胞增殖。在内皮细胞中，DAPK3通过蛋白激酶B途径调节过氧化物酶体增殖物激活受体γ共激活剂1α（PGC1α）的磷酸化和失活，从而促进细胞衰老，导致线粒体代谢相关基因的表达减少，例如ATP5G1、 BDNF 和 COX5A。我们的研究表明，DAPK3 参与细胞衰老和 PGC1α 调节，这表明 DAPK3 调节可能对于治疗与衰老相关的脑部疾病或对放射治疗的反应很重要。