肝脏X受体激动剂TO901317对APP/PS1双转基因阿尔茨海默病小鼠认知功能的影响及其机制  

Effect of liver X receptor agonist TO901317 on cognitive function in APP/PS1 double transgenic mice with Alzheimer’s disease and the underlying mechanism

作　　者：罗英茂[1] 谭小林[1] 张雄[2] 李远[1] 黄杰[1] 邓煜 LUO Yingmao;TAN Xiaolin;ZHANG Xiong;LI Yuan;HUANG Jie;DENG Yu(Department of Gerontology,Chongqing Mental Health Center,Chongqing 400010;Neuroscience ResearchCenter,School of Basic Medicine,Chongqing Medical University,Chongqing 400016,China)

机构地区：[1]重庆市精神卫生中心老年科,重庆400000 [2]重庆医科大学基础医学院神经科学研究中心,重庆400016

出　　处：《中南大学学报（医学版）》2022年第10期1324-1331,共8页Journal of Central South University ：Medical Science

基　　金：重庆市自然科学基金(Cstc2019jcyj-msxmX0673)。

摘　　要：目的:肝脏X受体(liver X receptor,LXR)是核受体超家族中的一员,其中LXR-β是脑细胞内胆固醇含量的重要感受器,而LXR-β/类视黄醇X受体(retinoic X receptor,RXR)-α/ATP结合盒转运子A1(ATP binding cassette transporter A1,ABCA1)胆固醇跨膜转运体系与阿尔茨海默病(Alzheimer’s disease,AD)的发生、发展密切相关。LXR激动剂TO901317能影响APP/PS1双转基因小鼠脑组织中β淀粉样蛋白(β-amyloid protein,Aβ)的生成,但其具体机制尚未阐明。本研究旨在观察LXR激动剂TO901317对高胆固醇饲料饲喂的AD小鼠的认知功能的影响,并从胆固醇代谢的角度探讨其可能的机制。方法:选取24只雄性6月龄APP/PS1双转基因AD小鼠,并随机分为4组,即普通饲料(control)组、高胆固醇饮食(cholesterol rich diet,CRD)组、CRD联合LXR激动剂TO901317饲喂组(TO901317组)以及CRD、TO901317联合LXR拮抗剂GSK2033饲喂组(GSK2033组),每组各6只。以CRD为基础饲料混合猪油、蛋黄粉、鱼肝油等加工制成的颗粒饲料,按每天两次饲喂小鼠;药物组在CRD的同时给予药物,TO901317及GSK2033溶解后均稀释至最终浓度0.03%,并按照小鼠体重通过胃管每日灌胃给药,各组总治疗时间为3个月。饲喂3个月后,采用Morris水迷宫实验观察各组小鼠空间探索和记忆能力的变化;酶标仪比色法检测各组小鼠血清中TC、LDL和HDL的含量;ELISA法检测各组AD小鼠脑组织中Aβ_(42)的表达情况;蛋白质印迹法检测各组小鼠脑组织LXR-β、RXR-α、ABCA1和Caveolin-1蛋白质水平的变化。结果:Morris水迷宫实验结果显示:与control组相比,CRD组小鼠穿越平台的次数、距离和时间均显著降低(均P<0.05);相较于CRD组,TO901317组小鼠穿越平台的次数、距离和时间显著增加(均P<0.05);而相较于TO901317组,GSK2033组上述指标均降低(均P<0.05)。酶标比色仪检测结果显示:CRD组小鼠血清中TC和LDL含量较control组显著增加,而HDL却显著减少(均P<0.001);TO9013Objective:The liver X receptors(LXRs)are members of the nuclear hormone receptor superfamily,and LXR-βis an important receptor for cholesterol content in brain cells.LXR-β/retinoic X receptor(RXR-α)/ATP binding cassette transporter A1(ABCA1)cholesterol transmembrane transport system is closely related to the occurrence and development of Alzheimer’s disease(AD).LXR agonist TO901317 can affect the accumulation ofβ-amyloid protein in the brain tissue of APP/PS1 double transgenic AD mice.However,the molecular mechanism is not clarified in detail.This study aims to evaluate the effects of LXR agonist TO901317 on the cognitive function of AD mice fed with high cholesterol diet,and to explore its possible mechanism from the perspective of cholesterol metabolism.Methods:Twenty four male 6-month-old APP/PS1 double transgenic AD mice were randomly divided into 4 groups,6 mice in each group:a control group(fed with normal diet),a cholesterol rich diet(CRD)group,a TO901317 group(fed with CRD combined with TO901317),and a GSK2033 group(fed with CRD combined with TO901317 and LXR antagonist GSK2033).The mice were fed with pellet feed made of high cholesterol feed,mixed with lard,egg yolk powder,and cod liver oil twice a day.TO901317 and GSK2033 were dissolved and diluted to a final concentration at 0.03%.The drugs were given to the mice daily through gastric tube according to their body weight.Meanwhile,the mice in the drug group were fed with high cholesterol diet.After feeding for 3 months,Morris water maze was used to observe the changes of spatial exploration and memory ability of AD mice in each group.The contents of TC,LDL,and HDL in serum of mice in each group were detected by cholesterol enzyme colorimetry,and the differences among the groups were compared.The expression of Aβ_(42) in the brain of AD mice was detected by ELISA.Western blotting was used to detect the protein levels of LXR-β,RXR-α,ABCA1,and Caveolin-1 in the brain of each group.Results:Morris water maze results showed that the times,distance an

关 键 词：肝脏X受体 TO901317 阿尔茨海默病 ABCA1跨膜转运体系 脂筏 AΒ42 

分 类 号：R749.16[医药卫生—神经病学与精神病学]