Effect of hesperetin in early intervention on Aβ transporter in APPswe / PS1d E9 mice

Abstract

Abstract: Objective To explore the effect of different doses of hesperetin early intervention on β-amyloid transporter in APPswe/PS1dE9 transgenic mice. Methods The 3-month-old C57BL/6J wild type mice were set up as the control group, the 3-month-old APPswe/PS1d E9 transgenic mice were randomly divided into the model group, hesperetin low-dose group, medium-dose group and high-dose groups (20, 40, 80 mg·kg^-1·d^-1), and gavage once a day for 6 months. Immunohistochemistry was applied to test the expression of insulin-degrading enzyme (IDE) in brain tissue, Western blotting (WB) was applied to detect receptor of advanced glycation endproducts (RAGE), low density lipoprotein receptor-associated protein 1 (LRP-1) , P-glycoprotein (P-gp) and the blood-brain barrier related proteins Claudin-5, Occludin and occlusive zonolin-1 (ZO-1). Results Compared with the model group, IDE expression was significantly enhanced in three hesperetin groups. Compared with the control group, the model group exhibited decreased expressions of P-gp and LRP-1, increased expression of RAGE, and decreased expressions of Claudin-5, Occludin, and ZO-1. In contrast, compared with the model group, the hesperetin groups showed increased expressions of P-gp and LRP-1, decreased expression of RAGE, and increased expressions of Claudin-5, Occludin, and ZO-1(P<0.05). Conclusion Early intervention of hesperetin in APPswe/PS1dE9 mice can affect Aβ metabolismand transport by enhancing IDE activity, regulating Aβ transporter and blood-brain barrier tightness.

Key words: Alzheimer's disease, hesperetin, blood-brain barrier, insulin-degrading enzyme, receptor of advanced glycation endproducts, P-glycoprotein

摘要： 目的研究不同剂量橙皮素早期干预APPswe/PS1d E9双转基因小鼠对β-淀粉样蛋白（Aβ）相关转运蛋白的影响。方法三月龄C57BL/6J野生型小鼠为对照组,三月龄APPswe/PS1d E9双转基因小鼠随机分为模型组、橙皮素低、中、高剂量组（20、40、80 mg·kg^-1·d^-1）,每天灌胃1次,连续6个月。免疫组织化学法测定脑组织中胰岛素降解酶（IDE）的表达,蛋白印迹法检测转运Aβ的相关蛋白晚期糖基化终产物（RAGE）、低密度脂蛋白受体相关蛋白1（LRP-1）、P-糖蛋白（P-gp）及血脑屏障（BBB）相关蛋白紧密连接蛋白-5（Claudin-5）、闭合蛋白（Occludin）、闭锁小带蛋白-1（ZO-1）的表达。结果与模型组相比,橙皮素三个剂量组IDE表达明显增强;与对照组相比,模型组P-gp和LRP-1表达减少,RAGE表达增加,Claudin-5、Occludin、ZO-1表达均减少;与模型组相比,橙皮素干预后P-gp和LRP-1表达增加,RAGE表达减少,Claudin-5、Occludin和ZO-1表达均增加（P<0.05）。结论橙皮素早期干预APPswe/PS1d E9小鼠可通过增强IDE活性、影响Aβ转运蛋白表达及血脑屏障紧密性,从而影响Aβ代谢和转运。

关键词: 阿尔茨海默病, 橙皮素, 血脑屏障, 胰岛素降解酶, 晚期糖基化终产物, P-糖蛋白

CLC Number:

R285.5

SUN Ying, WEN Hao, WANG Zhicheng, XU Wenfang, WANG Ruiting. Effect of hesperetin in early intervention on Aβ transporter in APPswe / PS1d E9 mice[J]. Journal of Chengde Medical University, 2025, 42(6): 451-456.

孙莹, 闻豪, 王志成, 徐文芳, 王瑞婷. 橙皮素早期干预APPswe/PS1d E9小鼠对Aβ转运蛋白的影响[J]. 承德医学院学报, 2025, 42(6): 451-456.

Add to citation manager EndNote|Ris|BibTeX

URL: http://tougao.cdmc.edu.cn:8088/EN/

http://tougao.cdmc.edu.cn:8088/EN/Y2025/V42/I6/451

References

[1] Jha NK, Nelson VK, Nuli MV, et al.Unveiling the impact of aging on bbb and alzheimer's disease: Factors and therapeutic implications[J]. Ageing Res Rev, 2024, 98: 102224.
[2] Tian Y, Jing G, Zhang M.Insulin-degrading enzyme: Roles and pathways in ameliorating cognitive impairment associated with alzheimer's disease and diabetes[J]. Ageing Res Rev, 2023, 90: 101999.
[3] Chen J, Xiang P, Duro-Castano A, et al.Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport[J]. Sig Transduct Target Ther, 2025, 10: 331.
[4] 王志成,董一峰,张子龙,等. β淀粉样蛋白的跨血脑屏障转运[J]. 承德医学院学报,2022,39(1):54-57.
[5] 苏嘉楠,安继仁,孙贵炎,等. 基于AMPK/mTOR信号通路探讨中药复方益糖康对db/db小鼠血脑屏障通透性及紧密连接蛋白的影响[J]. 辽宁中医药大学学报,2024,26(7):10-15.
[6] 冯旭,曾鑫,梁希瑶,等. 橙皮素药理活性以及开发技术的研究进展[J]. 广东化工,2023,50(22):74-75,66.
[7] 张子龙,王志成,董一峰,等. 橙皮素早期干预对APPswe/PS1dE9小鼠学习记忆能力及TLR2、NF-κB表达水平的影响[J]. 承德医学院学报,2020,37(3):188-191.
[8] 王志成,李宝群,吴晓光,等. 橙皮素早期干预对APPswe/PS1dE9小鼠学习记忆能力和Aβ42、NEP的影响[J]. 承德医学院学报,2021,38(6):458-463.
[9] 谢婷,徐采利,唐姣玲,等. 二甲双胍通过增强M146L细胞IDE表达促进胞内Aβ降解[J]. 中山大学学报(医学科学版),2022,43(4):522-529.
[10] 张爽曦,龙建纲,刘健康. 胰岛素降解酶与阿尔兹海默病的发生[J]. 中国生物化学与分子生物学报,2018,34(3):249-254.
[11] Rowland HA, Moxon SR, Corbett NJ, et al. Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-β deposition[J]. Neuronal Signal, 2023, 7(4): Ns20230016.
[12] Song ES, Juliano MA, Juliano L, et al.Substrate activation of insulin-degrading enzyme (insulysin). A potential target for drug development[J]. J Biol Chem, 2003, 278(50): 49789-49794.
[13] Gallagher JJ, Minogue AM, Lynch MA.Impaired performance of female APP/PS1 mice in the morris water maze is coupled with increased Aβ accumulation and microglial activation[J]. Neurodegener Dis, 2013, 11(1): 33-41.
[14] Peng Y, Hou C, Yang Z, et al.Hydroxytyrosol mildly improve cognitive function independent of app processing in APP/PS1 mice[J]. Mol Nutr Food Res, 2016, 60(11): 2331-2342.
[15] 刘晓琪. 丹参酮ⅡA通过上调Aβ降解酶改善阿尔茨海默病的机制研究[D]. 广州:广州中医药大学,2023.
[16] Hartz AM, Miller DS, Bauer B.Restoring blood-brain barrier p-glycoprotein reduces brain amyloid-beta in a mouse model of alzheimer's disease[J]. Mol Pharmacol, 2010, 77(5): 715-723.
[17] Petralla S, Panayotova M, Franchina E, et al.Low-density lipoprotein receptor-related protein 1 as a potential therapeutic target in alzheimer's disease[J]. Pharmaceutics, 2024, 16(7): 948.
[18] Chen Y, He Y, Han J, et al.Blood-brain barrier dysfunction and alzheimer's disease: Associations, pathogenic mechanisms and therapeutic potential[J]. Front Aging Neurosci, 2023, 15: 1258640.
[19] Miners JS, Schulz I, Love S.Differing associations between Aβ accumulation, hypoperfusion, blood-brain barrier dysfunction and loss of pdgfrb pericyte marker in the precuneus and parietal white matter in alzheimer's disease[J]. J Cereb Blood Flow Metab, 2018, 38(1): 103-115.
[20] Petrushanko IY, Mitkevich VA, Makarov AA.Effect of β-amyloid on blood-brain barrier properties and function[J]. Biophys Rev, 2023, 15(2): 183-197.
[21] Pyun J, Koay H, Runwal P, et al.Cu(ATSM) increases p-glycoprotein expression and function at the blood-brain barrier in C57BL6/J mice[J]. Pharmaceutics, 2023, 15(8): 15082084.
[22] 董一峰. 橙皮素早期干预对APPswe/PS1dE9双转基因小鼠Aβ生成的影响[D]. 承德:承德医学院,2019.
[23] Xing ZK, Du LS, Fang X, et al.The relationship among amyloid-β deposition, sphingomyelin level, and the expression and function of P-glycoprotein in Alzheimer’s disease pathological process[J]. Neural Regen Res, 2023, 18(6): 1300-1307.
[24] Zhang YL, Wang J, Zhang ZN, et al.The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer's disease[J]. Neural Regen Res, 2022, 17(11): 2355-2363.
[25] 万灿. 丹参酮ⅡA调控脑微血管内皮细胞SIRT1介导的内质网应激改善AD的作用与机制研究[D]. 广州:广州中医药大学,2022.
[26] Deane R, Singh I, Sagare AP, et al.A multimodal rage-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of alzheimer disease[J]. J Clin Invest, 2012, 122(4): 1377-1392.
[27] Dobrucki IT, Miskalis A, Nelappana M, et al.Receptor for advanced glycation end-products: Biological significance and imaging applications[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2024, 16(1): 1935.
[28] 黄冬,苗锐,李阳,等. 海马高级糖基化终末产物受体和β-淀粉样前体蛋白裂解酶表达增加与自发性高血压大鼠认知功能损害相关性研究[J]. 陕西医学杂志,2022,51(1):20-24.
[29] 董一峰,狄婷婷,徐树雷,等. 不同浓度Aβ25-35对小胶质细胞上RAGE/NF-κB信号通路的影响[J]. 中国老年学杂志,2019,39(14):3501-3505.
[30] Shi H, Koronyo Y, Fuchs DT, et al.Retinal arterial Aβ40 deposition is linked with tight junction loss and cerebral amyloid angiopathy in mci and ad patients[J]. Alzheimers Dement, 2023, 19(11): 5185-5197.
[31] 申杰,徐桂华. 阿尔茨海默病与血脑屏障的相关性研究进展[J]. 实用医学杂志,2024,40(11):1602-1606.
[32] Deepika, Maurya PK.Health benefits of quercetin in age-related diseases[J]. Molecules, 2022, 27(8): 2498.
[33] 张泽,韩锟,贾宁. 荭草苷对APP/PS1转基因小鼠神经保护作用实验研究[J]. 陕西医学杂志,2020,49(5):534-537.
[34] 李可,苗果,柳秋,等. 灯盏乙素通过细胞转运途径对阿尔茨海默病大鼠β-淀粉样蛋白跨血脑屏障的影响[J]. 中西医结合心脑血管病杂志,2024,22(10):1782-1786.
[35] 高欣,刘俊君,荆尚文,等. 基于网络药理学和细胞实验探讨橙皮素对LPS诱导的小胶质细胞炎症模型的改善作用[J]. 中成药,2024,46(5):1707-1715.