Legumain knockout improved cognitive impairment via reducing neuroinflammation in right unilateral common carotid artery occlusion mice,Life Sciences

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Legumain knockout improved cognitive impairment via reducing neuroinflammation in right unilateral common carotid artery occlusion mice
Life Sciences ( IF 5.2 ) Pub Date : 2021-09-10 , DOI: 10.1016/j.lfs.2021.119944
Xueqing Chai ₁ , Xiaolin Li ₁ , Wenxin Zhang ₁ , Xiaoyue Tan ₁ , Haiyun Wang ₂ , Zhuo Yang ₁

Affiliation

Aims

Chronic cerebral hypoperfusion (CCH) is a state of chronic cerebral blood flow reduction, and it is the main cause of cognitive impairment and neurodegenerative diseases. The abnormal upregulation of legumain, a lysosomal cysteine protease, trigger synaptic plasticity impairment and neuroinflammation, which are involved in the underlying pathophysiology of CCH. At present, few studies have reported the role of legumain in cognitive impairment caused by CCH. In our study, we aimed to investigate the involvement of legumain knockout in cognitive function and neuroinflammation in a CCH mouse model.

Main methods

In this study, right unilateral common carotid artery occlusion (rUCCAO) was used to simulate the pathological state of cerebral ischemic injury. Various behavioural tests were executed to assess cognitive performance. In vivo electrophysiological recordings were used to measure synaptic functions. Western blotting, Golgi staining, haematoxylin/eosin staining, and immunofluorescence assays were conducted to examine pathological changes and molecular mechanisms.

Key findings

The data showed that the level of legumain was significantly increased in the hippocampus of mice subjected to rUCCAO. Legumain knockout significantly improved cognitive function and synaptic plasticity induced by rUCCAO, suggesting that legumain knockout-regulation effectively protected against CCH-induced behavioural dysfunctions. Moreover, legumain knockout suppressed rUCCAO-induced microglial activation, reduced the abnormal expression of inflammatory cytokines and the inflammasome complex, and impeded the activation of P65 and pyroptosis.

Significance

These findings suggest that legumain is an effective regulator of CCH, and may be an ideal target for the development of cerebral ischemia treatments in the future.

中文翻译：

Legumain 敲除通过减少右侧单侧颈总动脉闭塞小鼠的神经炎症改善认知障碍

宗旨

慢性脑灌注不足（CCH）是一种慢性脑血流量减少的状态，是导致认知障碍和神经退行性疾病的主要原因。Legumain（一种溶酶体半胱氨酸蛋白酶）的异常上调会引发突触可塑性损伤和神经炎症，这与 CCH 的潜在病理生理学有关。目前，很少有研究报道legumain在CCH引起的认知障碍中的作用。在我们的研究中，我们旨在调查在 CCH 小鼠模型中，legumain 基因敲除对认知功能和神经炎症的影响。

主要方法

本研究采用右侧单侧颈总动脉闭塞术（rUCCAO）模拟脑缺血损伤的病理状态。执行各种行为测试以评估认知表现。体内电生理记录用于测量突触功能。进行蛋白质印迹、高尔基体染色、苏木精/伊红染色和免疫荧光测定以检查病理变化和分子机制。

主要发现

数据显示，接受rUCCAO的小鼠海马中legumain的水平显着增加。Legumain 敲除显着改善了 rUCCAO 诱导的认知功能和突触可塑性，表明legumain 敲除调节有效地防止了 CCH 引起的行为功能障碍。此外，legumain 敲除抑制了 rUCCAO 诱导的小胶质细胞激活，减少了炎症细胞因子和炎性体复合物的异常表达，并阻碍了 P65 的激活和细胞焦亡。