Shang Dongsheng, Hong Yin, Xie Wangwang, Tu Zhigang, Xu Jun
Institute of Life Sciences, Jiangsu University, Zhenjiang, China.
China National Clinical Research Center for Neurological Diseases (NCRC-ND), Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Front Neurol. 2020 Aug 27;11:929. doi: 10.3389/fneur.2020.00929. eCollection 2020.
Alzheimer's disease (AD) is the leading cause of dementia. With no reliable treatment that delays or reverses the progress of AD, effective medical drugs, and interventions for AD treatment are in urgent need. Clinical success for patients thus relies on gaining a clearer understanding of AD pathogenesis to feed the development of novel and potent therapy strategies. It is well-established that inflammatory processes are involved in the pathology of AD, and recent studies implicated senescence of glial cells as an important player in the progression of AD. We did a preliminary screen in rat astrocytes for the five most abundant inflammatory factors in neuroinflammation, namely IL-1β, IL-6, IL-8, TGF-β1, and TNF-α, and found that IL-1β could efficiently induce cellular senescence. After that, SA-β-gal staining, immunofluorescence, ELISA, qRT-PCR, and immunoblotting were used to explore the underlying mechanism through which IL-1β mediates cellular senescence of rat astrocytes. IL-1β-induced cellular senescence of rat astrocytes was accompanied by increased total and phosphorylated tau. Further experiments showed that both oligomerized amyloid β (Aβ) and HO treatment can induce cellular senescence in rat astrocytes and increase the production and secretion of IL-1β from these cells. Subsequent mechanistic study revealed that activation of NLRP3 mediates Aβ and HO-induced maturation and secretion of IL-1β. Our results suggest that IL-1β mediates senescence in rat astrocytes induced by several common adverse stimuli in AD, implicating IL-1β and NLRP3 as valuable diagnostic biomarkers and therapeutic targets for AD.
阿尔茨海默病（AD）是痴呆症的主要病因。由于没有可靠的治疗方法能够延缓或逆转AD的进展，因此迫切需要有效的治疗药物和干预措施来治疗AD。因此，患者的临床成功依赖于更清楚地了解AD的发病机制，以推动新型有效治疗策略的发展。众所周知，炎症过程参与了AD的病理过程，最近的研究表明神经胶质细胞衰老在AD进展中起重要作用。我们在大鼠星形胶质细胞中对神经炎症中五种最丰富的炎症因子，即白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、转化生长因子-β1（TGF-β1）和肿瘤坏死因子-α（TNF-α）进行了初步筛选，发现IL-1β能够有效诱导细胞衰老。此后，通过β-半乳糖苷酶（SA-β-gal）染色、免疫荧光、酶联免疫吸附测定（ELISA）、实时定量聚合酶链反应（qRT-PCR）和免疫印迹法，探讨IL-1β介导大鼠星形胶质细胞衰老的潜在机制。IL-1β诱导的大鼠星形胶质细胞衰老伴随着总tau蛋白和磷酸化tau蛋白的增加。进一步的实验表明，寡聚化淀粉样β蛋白（Aβ）和血红素加氧酶（HO）处理均可诱导大鼠星形胶质细胞衰老，并增加这些细胞中IL-1β的产生和分泌。随后的机制研究表明，NLRP3炎性小体的激活介导了Aβ和HO诱导的IL-1β成熟和分泌。我们的结果表明，IL-1β介导了AD中几种常见不良刺激诱导的大鼠星形胶质细胞衰老，这意味着IL-1β和NLRP3炎性小体是AD有价值的诊断生物标志物和治疗靶点。
