Yang Na, Lin Ke, Zhang Jie, Wang Jinping, Meng Tao, Zhu Jie, Yang Liu, Zhou Yueqin
{"title":"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。","authors":"Yang Na, Lin Ke, Zhang Jie, Wang Jinping, Meng Tao, Zhu Jie, Yang Liu, Zhou Yueqin","doi":"10.1080/0361073X.2022.2095605","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":12240,"journal":{"name":"Experimental Aging Research","volume":null,"pages":null},"PeriodicalIF":1.4000,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"Yang Na, Lin Ke, Zhang Jie, Wang Jinping, Meng Tao, Zhu Jie, Yang Liu, Zhou Yueqin\",\"doi\":\"10.1080/0361073X.2022.2095605\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":12240,\"journal\":{\"name\":\"Experimental Aging Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.4000,\"publicationDate\":\"2023-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Aging Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/0361073X.2022.2095605\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/7/6 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q4\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Aging Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/0361073X.2022.2095605","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/7/6 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
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.
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.