Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Graduate Training Program of Korean Medicine for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.
Department of Pharmacology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.
Brain Behav Immun. 2020 Jul;87:765-776. doi: 10.1016/j.bbi.2020.03.011. Epub 2020 Mar 19.
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 test and impaired spatial learning and memory functions in Morris water maze test 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.
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），但其发病机制尚不清楚。我们在这里使用 45 分钟大脑中动脉闭塞（MCAO）/再灌注诱导的 PSCI 模型，探讨了中风后炎症小体在长期 PSCI 发展中的作用。在中风后第 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。在老年小鼠大脑中评估炎症小体传感器基因表达，发现黑色素瘤缺失 2（Aim2）在 6、12 和 18 月龄的小鼠大脑中表达占主导地位。AIM2 mRNA 和蛋白增加直至中风后 7 天。PSCI 在高架十字迷宫测试中降低了焦虑，在 Morris 水迷宫测试中 28 天后损害了空间学习和记忆功能。中风后 7 天，PSCI 组海马体和皮质中的 AIM2 和其他炎症小体亚基免疫反应性，包括半胱氨酸天冬氨酸蛋白酶-1（caspase-1）、白细胞介素（IL）-1β和 IL-18，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，但与 NeuN（神经元标志物）和 GFAP（星形胶质细胞标志物）免疫反应性不共定位，表明小胶质细胞或内皮细胞诱导的 AIM2 产生介导了 PSCI 的发病机制。此外，炎症小体诱导的细胞焦亡可能导致中风后急性和慢性神经元死亡。在小鼠中，AIM2 敲除（KO）和 Ac-YVAD-CMK 诱导的 caspase-1 抑制显著改善了认知功能，并逆转了海马体的脑容量，相对于中风小鼠而言。总之，AIM2 炎症小体介导的炎症和细胞焦亡可能加重了 PSCI；因此，靶向和控制 AIM2 炎症小体可能治疗 PSCI。
