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组织蛋白酶K通过焦亡通路影响血管性痴呆模型大鼠学习记忆功能

裘佳瑶^1,2, 陈丽³, 王心怡⁴, 奚培焱², 李伟健², 张浩楠², 何治², 姜海英^2,*

¹浙江理工大学，杭州 310000；²嘉兴大学医学院，嘉兴 314001；³云南省滇东北中心医院，昭通 657000；⁴复旦大学脑科学研究院，上海 200032

摘要

本研究旨在探讨组织蛋白酶K (cathepsin K, CatK)影响血管性痴呆(vascular dementia, VD)模型大鼠海马学习记忆功能障碍的作用机制。Sprague-Dawley (SD)雄性大鼠随机分为对照组(Control)、对照+CatK 阻断剂组(Control+CatKII)、VD模型组(VD)以及VD模型+CatK阻断剂组(VD+CatKII)。利用改良的双侧颈总动脉永久性结扎法建立VD模型4 周后，海马齿状回区微量注射CatK 阻断剂Ⅱ (CatK inhibitor Ⅱ, CatKII)或等量人工脑脊液；利用HT22 细胞构建氧糖剥夺细胞模型。Morris 水迷宫(Morris water maze, MWM)实验观察大鼠空间学习记忆能力，应用Western blot 法检测CatK、NLRP3、GSDMD、Caspase-1等相关信号蛋白的表达水平。结果显示，在MWM定位航行实验中，VD组每日逃避潜伏期相比Control组均明显延长；VD+CatKII 组与VD组相比第3 天和第4 天的逃避潜伏期显著缩短(P < 0.05)。MWM空间探索实验显示，VD组穿越原平台区次数和目标象限停留时间百分比显著少于Control 组(P < 0.05)，而VD+CatKII 组与VD组相比均显著增加(P < 0.05)。Western blot法观察到，与VD组相比，VD+CatKII 组的NLRP3、GSDMD、Caspase-1、IL-18、IL-1β 等细胞焦亡相关蛋白表达均明显减少(P < 0.05)。氧糖剥夺细胞实验同样观察到，药理学或基因干扰方法抑制CatK时均显著降低Caspase-1 等焦亡相关蛋白表达水平。以上结果表明，CatK 影响VD模型大鼠的学习记忆功能，抑制CatK 通过调控细胞焦亡通路改善VD模型大鼠的学习记忆障碍。

关键词： 组织蛋白酶K; 血管性痴呆; 细胞焦亡; 学习记忆

Inhibition of cathepsin K improves the learning and memory function of the vascular dementia model rats through blocking pyroptosis pathway

QIU Jia-Yao^1,2, CHEN Li³, WANG Xin-Yi⁴, XI Pei-Yan², LI Wei-Jian², ZHANG Hao-Nan², HE Zhi², JIANG Hai-Ying^2,*

¹Zhejiang Sci-Tech University, Hangzhou 310000, China；²Jiaxing University College of Medicine, Jiaxing 314001, China；³Northeast Yunnan Regional Central Hospital, Zhaotong 657000, China；⁴Institutes of Brain Science, Fudan University, Shanghai 200032, China

Abstract

The study aimed to investigate the mechanism of cathepsin K (CatK) on hippocampal learning and memory dysfunction in rats with vascular dementia (VD). Sprague-Dawley (SD) male rats were randomly divided into control group (Control), control+ CatK blocker group (Control+CatK

The study aimed to investigate the mechanism of cathepsin K (CatK) on hippocampal learning and memory dysfunction in rats with vascular dementia (VD). Sprague-Dawley (SD) male rats were randomly divided into control group (Control), control+ CatK blocker group (Control+CatKⅡ), VD model group (VD), and VD model + CatK blocker group (VD+CatKⅡ). Four weeks after the establishment of the VD model by permanent ligation of bilateral common carotid arteries, CatK inhibitor Ⅱ (CatKⅡ) or equivalent artificial cerebrospinal fluid was injected into the dentate gyrus of hippocampus. Oxygen glucose deprivation (OGD) cell model was established using the HT22 cells. Morris water maze (MWM) experiment was used to observe the spatial learning and memory abilities of rats, and the expression levels of CatK, NLRP3, GSDMD, Caspase-1 and other pyroptosis-related proteins were detected by Western blot assay. The MWM place navigation test showed that the daily escape latency of the VD group was significantly longer than that of the Control group. The escape latency of the VD+CatKⅡ group was significantly shorter than that of the VD group on days 3 and 4 (P < 0.05). The space exploration test showed that the frequency of crossing the original platform area and the percentage of residence time in the target quadrant in the VD group were significantly less than those in the Control group (P < 0.05), while those in the VD+CatKⅡ group were significantly increased compared with the VD group (P < 0.05). Western blot analysis showed that the expression of NLRP3, GSDMD, Caspase-1, IL-18 and IL-1β in the VD+CatKⅡ group was significantly decreased compared with those in the VD group (P < 0.05). It was also observed in the OGD HT22 cell experiment that the levels of Caspase-1 and other pyroptosis-related proteins were significantly decreased when CatK was inhibited by pharmacological or gene interference methods. In conclusion, CatK can affect the learning and memory function of VD model rats. Inhibition of CatK can attenuate cell pyroptosis pathway to improve the learning and memory impairment of the VD model rats.

Key words: cathepsin K; vascular dementia; cell pyroptosis; learning and memory

收稿日期：　　录用日期：

通讯作者：姜海英　　E-mail:

DOI: 10.13294/j.aps.2026.0033

引用本文：

裘佳瑶, 陈丽, 王心怡, 奚培焱, 李伟健, 张浩楠, 何治, 姜海英. 组织蛋白酶K通过焦亡通路影响血管性痴呆模型大鼠学习记忆功能[J]. 生理学报 2026; 78 (2): 425-432.

QIU Jia-Yao, CHEN Li, WANG Xin-Yi, XI Pei-Yan, LI Wei-Jian, ZHANG Hao-Nan, HE Zhi, JIANG Hai-Ying. Inhibition of cathepsin K improves the learning and memory function of the vascular dementia model rats through blocking pyroptosis pathway. Acta Physiol Sin 2026; 78 (2): 425-432 (in Chinese with English abstract).