Aging, Plasminogen Activator Inhibitor 1, Brain Cell Senescence, and Alzheimer's Disease.
Aging, Plasminogen Activator Inhibitor 1, Brain Cell Senescence, and Alzheimer's Disease.
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DOI：
10.14336/ad.2022.1220
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发表时间：
2023-04-01
影响因子：
7.4
通讯作者：
Liu, Rui-Ming
中科院分区：
文献类型：
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作者：
Jiang, Chun-Sun;Rana, Tapasi;Jin, Lee-Way;Farr, Susan A.;Morley, John E.;Qin, Hongwei;Liu, Gang;Liu, Rui-Ming
迟发性阿尔茨海默病（LOAD）占阿尔茨海默病（AD）病例的>95%，其病因学尚不清楚。新出现的证据表明，细胞衰老对AD病理生理学有重要贡献，尽管脑细胞衰老的潜在机制以及衰老细胞促进神经病理生理学的机制仍不清楚。在这项研究中，我们首次表明，纤溶酶原激活物抑制剂1（派-1），丝氨酸蛋白酶抑制剂的表达增加，与细胞周期抑制因子p53和p21的表达增加，在海马/皮质的衰老加速小鼠倾向8（SAMP 8）小鼠和LOAD患者。双重免疫染色结果显示，与相应对照中的星形胶质细胞相比，LOAD患者和SAMP 8小鼠脑中的星形胶质细胞表达更高水平的衰老标记物和派-1。体外研究进一步表明，在原代小鼠和人星形胶质细胞中，派-1单独过表达，细胞内或细胞外，诱导衰老，而抑制或沉默派-1减弱H2 O2诱导的衰老。衰老星形胶质细胞的条件培养液（CM）可诱导神经元凋亡。重要的是，与来自过表达野生型派-1（wtPAI-1）的衰老星形胶质细胞的含有派-1的CM相比，来自过表达分泌缺陷型派-1（sdPAI-1）的衰老星形胶质细胞的派-1缺陷型CM对神经元的作用显著降低，尽管sdPAI-1和wtPAI-1诱导相似程度的星形胶质细胞衰老。总之，我们的研究结果表明，增加派-1，细胞内或细胞外，可能有助于脑细胞衰老的负载和衰老的星形胶质细胞可以诱导神经元凋亡，通过分泌病理活性分子，包括派-1。
The etiology for late-onset Alzheimer’s disease (LOAD), which accounts for >95% of Alzheimer’s disease (AD) cases, is unknown. Emerging evidence suggests that cellular senescence contributes importantly to AD pathophysiology, although the mechanisms underlying brain cell senescence and by which senescent cells promote neuro-pathophysiology remain unclear. In this study we show for the first time that the expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, is increased, in correlation with the increased expression of cell cycle repressors p53 and p21, in the hippocampus/cortex of senescence accelerated mouse prone 8 (SAMP8) mice and LOAD patients. Double immunostaining results show that astrocytes in the brain of LOAD patients and SAMP8 mice express higher levels of senescent markers and PAI-1, compared to astrocytes in the corresponding controls. In vitro studies further show that overexpression of PAI-1 alone, intracellularly or extracellularly, induced senescence, whereas inhibition or silencing PAI-1 attenuated H2O2-induced senescence, in primary mouse and human astrocytes. Treatment with the conditional medium (CM) from senescent astrocytes induced neuron apoptosis. Importantly, the PAI-1 deficient CM from senescent astrocytes that overexpress a secretion deficient PAI-1 (sdPAI-1) has significantly reduced effect on neurons, compared to the PAI-1 containing CM from senescent astrocytes overexpressing wild type PAI-1 (wtPAI-1), although sdPAI-1 and wtPAI-1 induce similar degree of astrocyte senescence. Together, our results suggest that increased PAI-1, intracellularly or extracellularly, may contribute to brain cell senescence in LOAD and that senescent astrocytes can induce neuron apoptosis through secreting pathologically active molecules, including PAI-1.