Jiang Chun-Sun, Rana Tapasi, Jin Lee-Way, Farr Susan A, Morley John E, Qin Hongwei, Liu Gang, Liu Rui-Ming
1Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
1Department of Pathology and Laboratory Medicine, University of California, Davis, CA, USA.
Aging Dis. 2023 Apr 1;14(2):515-528. doi: 10.14336/AD.2022.1220.
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 HO-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.
晚发性阿尔茨海默病（LOAD）占阿尔茨海默病（AD）病例的95%以上，其病因尚不清楚。新出现的证据表明，细胞衰老对AD病理生理过程有重要影响，尽管脑细胞衰老的机制以及衰老细胞促进神经病理生理的机制仍不清楚。在本研究中，我们首次发现，丝氨酸蛋白酶抑制剂纤溶酶原激活物抑制剂1（PAI-1）在衰老加速小鼠8型（SAMP8）和LOAD患者的海马体/皮质中的表达增加，且与细胞周期抑制因子p53和p21表达的增加相关。双重免疫染色结果显示，与相应对照组的星形胶质细胞相比，LOAD患者和SAMP8小鼠大脑中的星形胶质细胞表达更高水平的衰老标志物和PAI-1。体外研究进一步表明，单独在细胞内或细胞外过表达PAI-1可诱导衰老，而抑制或沉默PAI-1可减轻过氧化氢（HO）诱导的原代小鼠和人星形胶质细胞衰老。用衰老星形胶质细胞的条件培养基（CM）处理可诱导神经元凋亡。重要的是，与过表达野生型PAI-1（wtPAI-1）的衰老星形胶质细胞含PAI-1的CM相比，过表达分泌缺陷型PAI-1（sdPAI-1）的衰老星形胶质细胞的PAI-1缺陷型CM对神经元的影响显著降低，尽管sdPAI-1和wtPAI-1诱导的星形胶质细胞衰老程度相似。总之，我们的结果表明，细胞内或细胞外PAI-1的增加可能导致LOAD中的脑细胞衰老，并且衰老的星形胶质细胞可通过分泌包括PAI-1在内的具有病理活性的分子诱导神经元凋亡。
