Although over one-third of stroke patients may develop post-stroke cognitive impairment (PSCI), the mechanisms underlying PSCI remain unclear. We explored here, the involvement of post-stroke inflammasomes in long-term PSCI development, using a 45 min-middle cerebral artery occlusion (MCAO)/reperfusion-induced PSCI model. Immunohistological assessment on day 1, 3, and 7 was followed by cognitive function test 28 days post-stroke. Evaluation of inflammasome sensor gene expression in aged mouse brains showed dominant expression of absent in melanoma 2 (Aim2) in 6-, 12-, and 18-month-old mouse brains. AIM2 mRNA and protein increased until 7 days post-stroke. PSCI decreased anxiety in elevated plus maze tests and impaired spatial learning and memory functions in Morris water maze tests 28 days post-stroke. AIM2 and other inflammasome subunit immunoreactivities, including those for caspase-1, interleukin (IL)-1β, and IL-18, were higher in the hippocampus and cortex of the PSCI than in those of the sham group 7 days post-stroke. AIM2 immunoreactivity of the PSCI group was primarily co-localized with Iba-1 (microglial marker) and CD31 (endothelial cell marker) immunoreactivities but not NeuN (neuronal marker) and GFAP (astrocyte marker) immunoreactivities, suggesting that microglia or endothelial cell-induced AIM2 production mediated PSCI pathogenesis. Additionally, inflammasome-induced pyroptosis might contribute to acute and chronic neuronal death after stroke. AIM2 knockout (KO) and Ac-YVAD-CMK-induced caspase-1 inhibition in mice significantly improved cognitive function and reversed brain volume in the hippocampus relative to those in stroke mice. Conclusively, AIM2 inflammasome-mediated inflammation and pyroptosis likely aggravated PSCI; therefore, targeting and controlling AIM2 inflammasome could potentially treat PSCI.

中文翻译：

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AIM2炎症小体导致小鼠脑损伤和慢性中风后认知障碍

尽管超过三分之一的中风患者可能会出现中风后认知障碍 (PSCI)，但 PSCI 的潜在机制仍不清楚。我们在这里探讨了中风后炎症小体在长期 PSCI 发展中的作用，使用 45 分钟大脑中动脉闭塞 (MCAO)/再灌注诱导的 PSCI 模型。在第 1、3 和 7 天进行免疫组织学评估，然后在中风后 28 天进行认知功能测试。对老年小鼠大脑中炎性体传感器基因表达的评估显示，在 6、12 和 18 个月大的小鼠大脑中，黑色素瘤 2 (Aim2) 中缺失的显性表达。AIM2 mRNA 和蛋白质增加至中风后 7 天。PSCI 降低了高架十字迷宫测试中的焦虑，并在中风后 28 天的 Morris 水迷宫测试中降低了空间学习和记忆功能。卒中后 7 天，PSCI 的海马和皮质中的 AIM2 和其他炎性体亚基免疫反应性，包括对 caspase-1、白细胞介素 (IL)-1β 和 IL-18 的免疫反应性高于假手术组。PSCI 组的 AIM2 免疫反应性主要与 Iba-1（小胶质细胞标志物）和 CD31（内皮细胞标志物）免疫反应性共定位，但不是 NeuN（神经元标志物）和 GFAP（星形胶质细胞标志物）免疫反应性，表明小胶质细胞或内皮细胞诱导AIM2 产生介导 PSCI 发病机制。此外，炎症小体诱导的细胞焦亡可能导致中风后的急性和慢性神经元死亡。与中风小鼠相比，AIM2 敲除 (KO) 和 Ac-YVAD-CMK 诱导的小鼠 caspase-1 抑制显着改善了海马的认知功能并逆转了脑容量。最终，AIM2 炎症小体介导的炎症和细胞焦亡可能加重 PSCI。因此，靶向和控制 AIM2 炎症小体可能会治疗 PSCI。