LXR激动剂TO901317对富含胆固醇饮食诱导的AD转基因小鼠认知障碍的改善与激活LXR-β-RXR-α-ABCA1跨膜转运系统和改善脂质筏的组成有关。

IF 1.4 4区 医学 Q4 GERIATRICS & GERONTOLOGY
Experimental Aging Research Pub Date : 2023-05-01 Epub Date: 2022-07-06 DOI:10.1080/0361073X.2022.2095605
Yang Na, Lin Ke, Zhang Jie, Wang Jinping, Meng Tao, Zhu Jie, Yang Liu, Zhou Yueqin
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引用次数: 0

摘要

背景:据报道,LXR激动剂在体内和体外实验中可抑制Aβ生成,缓解Aβ诱导的各种不良反应,但其机制尚未明确。本研究旨在观察LXR激动剂TO901317对富含胆固醇饮食(CRD)喂养的AD转基因小鼠认知功能的影响,并探讨其可能的机制。方法:选取32只6月龄雄性双转基因AD小鼠,随机分为4组:对照组(正常饮食)、CRD治疗组、TO901317治疗组和GSK2033治疗组。3个月后,用莫里斯水迷宫检测小鼠空间探索和记忆能力的变化;用ELISA检测脑内Aβ42的生成;用胆固醇酶比色法检测血清中总胆固醇(TC)、低密度脂蛋白(LDL)和高密度脂蛋白(HDL)的浓度;最后,用Western印迹法检测脑内LXR-β、RXR-α、ABCA1、caveolin-1、BACE1和APP在蛋白水平上的表达。结果与对照组相比,CRD 组小鼠的学习能力、记忆能力和空间探索能力明显下降(PConclusions:TO901317减轻了CRD诱导的转基因AD小鼠更严重的空间探索、学习和记忆障碍,其机制可能是TO901317能激活LXR-β/RXR-α/ABCA1跨膜转运系统,促进胆固醇外流,减少洞穴素-1、APP和BACE1,进一步减少脑内Aβ42。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Amelioration of Cholesterol Rich diet-induced Impaired Cognition in AD Transgenic Mice by an LXR Agonist TO901317 Is Associated with the Activation of the LXR-β-RXR-α-ABCA1 Transmembrane Transport System and Improving the Composition of Lipid Raft.

Background: It has been reported that LXR agonist can inhibit Aβ generation and alleviate Aβ-induced various adverse reactions in vivo and in vitro experiments, but the mechanisms have not been clarified. The study aimed to observe the effect of LXR agonist TO901317 on the cognitive function of AD transgenic mice fed with cholesterol-rich diet (CRD), and to explore the possible mechanism. Methods: 32 male 6-month-old double transgenic AD mice were enrolled and randomly divided into 4 groups: control (normal diet) group, CRD treatment group, TO901317 treatment group and GSK2033 treatment group. After 3 month, Morris water maze was for the changes of spatial exploration and memory ability; ELISA was for detecting the production of Aβ42 in the brain; the concentration of total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) in serum were detected by cholesterol enzyme colorimetry; Finally, the expression of LXR-β, RXR-α, ABCA1, caveolin-1, BACE1 and APP at protein level in the brains was measured by Western blotting.

Results: Compared with the control group, the learning, memory ability and spatial exploration ability of the mice were more significantly serious in the CRD group (P<0.05); The contents of TC and LDL in the serum and the production of Aβ42 in the brains were significantly increased (P<0.05), but HDL was remarkably decreased (P<0.05); The protein levels of LXR-β, RXR-α and ABCA1 were also significantly decreased (P<0.05); The expression of caveolin-1, APP and BACE1 were evidently increased (P<0.05). However, after treatment with TO901317, the impaired learning and memory and spatial exploration ability of the mice were significantly improved (P<0.05); The contents of TC and LDL in serum and the production of Aβ42 in the brains were significantly decreased (P<0.05), but HLD was increased (P<0.05); The protein levels of LXR-β, RXR-α, ABCA1were all significantly increased (P<0.05), while, the expression of caveolin-1, APP and BACE1 were all significantly decreased (P<0.05). All the changes were reversed by GSK2033 (P<0.05).

Conclusions: TO901317 attenuated the more serious impairment of spatial exploration, learning and memory in transgenic AD mice induced by CRD, and the mechanism may be that TO901317 could activate the LXR-β/RXR-α/ABCA1 transmembrane transport system, promote the cholesterol efflux, and decreased caveolin-1, APP and BACE1, further reduce Aβ42 in the brains.

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来源期刊
Experimental Aging Research
Experimental Aging Research 医学-老年医学
CiteScore
3.60
自引率
0.00%
发文量
68
审稿时长
>12 weeks
期刊介绍: Experimental Aging Research is a life span developmental and aging journal dealing with research on the aging process from a psychological and psychobiological perspective. It meets the need for a scholarly journal with refereed scientific papers dealing with age differences and age changes at any point in the adult life span. Areas of major focus include experimental psychology, neuropsychology, psychobiology, work research, ergonomics, and behavioral medicine. Original research, book reviews, monographs, and papers covering special topics are published.
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