Abstract

Cerebral small vessel disease (CSVD) is increasingly being recognized as a leading contributor to cognitive impairment in the elderly. However, there is a lack of effective preventative or therapeutic options for CSVD. In this exploratory study, we investigated the interplay between neuroinflammation and CSVD pathogenesis as well as the cognitive performance, focusing on NLRP3 signaling as a new therapeutic target. Spontaneously hypertensive stroke-prone (SHRSP) rats served as a CSVD model. We found that SHRSP rats showed decline in learning and memory abilities using morris water maze test. Activated NLRP3 signaling and an increased expression of the downstream pro-inflammatory factors, including IL (interleukin)-6 and tumor necrosis factor α were determined. We also observed a remarkable increase in the production of pyroptosis executive protein gasdermin D, and elevated astrocytic and microglial activation. In addition, we identify several neuropathological hallmarks of CSVD, including blood-brain barrier breakdown, white matter damage, and endothelial dysfunction. These results were in correlation with the activation of NLRP3 inflammasome. Thus, our findings reveal that the NLRP3-mediated inflammatory pathway could play a central role in the pathogenesis of CSVD, presenting a novel target for potential CSVD treatment.

中文翻译：

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脑小血管疾病大鼠模型中NLRP3炎症小体的激活

摘要

脑小血管疾病（CSVD）越来越被认为是导致老年人认知障碍的主要原因。然而，脑小血管病缺乏有效的预防或治疗方案。在这项探索性研究中，我们研究了神经炎症与 CSVD 发病机制以及认知表现之间的相互作用，重点关注 NLRP3 信号传导作为新的治疗靶点。自发性高血压脑卒中 (SHRSP) 大鼠作为 CSVD 模型。我们通过莫里斯水迷宫测试发现SHRSP大鼠的学习和记忆能力下降。确定了 NLRP3 信号传导的激活和下游促炎因子（包括 IL（白细胞介素）-6 和肿瘤坏死因子 α）表达的增加。我们还观察到焦亡执行蛋白gasdermin D 的产生显着增加，星形胶质细胞和小胶质细胞的激活也增加。此外，我们还发现了脑小血管病的几个神经病理学特征，包括血脑屏障破坏、白质损伤和内皮功能障碍。这些结果与 NLRP3 炎性体的激活相关。因此，我们的研究结果表明，NLRP3 介导的炎症通路可能在 CSVD 的发病机制中发挥核心作用，为潜在的 CSVD 治疗提供了一个新的靶点。