长期淫羊藿苷治疗对APP/PS1小鼠神经炎症的影响

doi:10.6040/j.issn.1671-7554.0.2019.1458

摘要/Abstract

摘要： 目的研究长期淫羊藿苷(ICA)治疗对阿尔茨海默病(AD)模型APP/PS1转基因小鼠认知功能、病理改变和神经炎症的影响,并探讨其中的作用机制。方法 Morris水迷宫试验检测ICA对小鼠学习记忆和空间认知能力的影响;免疫组织化学染色法检测ICA对小鼠海马区β淀粉样蛋白(Aβ)沉积、胶质细胞激活、炎性因子生成的影响;Western blotting法测定炎性信号反应通路NF-κB相关通路蛋白表达水平的变化。结果 (1)ICA可以减少APP/PS1小鼠逃避潜伏期(F第4天=4.96,P=0.017;F第5天=9.37,P=0.001),增加目标象限停留时间(F=9.31,P=0.001);(2)ICA可以减少APP/PS1小鼠海马区Aβ沉积(F_Aβarea=153.28,P<0.001;F_{Aβ IOD}=87.18,P<0.001);(3)ICA可以抑制APP/PS1小鼠神经细胞标记物GFAP和Iba-1的表达(F_GFAP=370.16,P<0.001;F_Iba-1=32.11,P<0.001)以及促炎性细胞因子白介素-1β(IL-1β)的生成(F=190.10,P<0.001);(4)ICA可以降低APP/PS1小鼠NF-κB通路蛋白p-p65/p65比值(F=338.77,P<0.001)。结论长期淫羊藿苷治疗可以通过抑制脑内胶质细胞激活,减少促炎因子生成和海马区Aβ沉积,改善APP/PS1小鼠认知功能。

关键词: 阿尔茨海默病, 淫羊藿苷, β淀粉样蛋白, APP/PS1转基因小鼠, 神经炎症

Abstract: Objective To study the effects of long-term icariin(ICA)treatment on cognitive function, pathological changes and neuroinflammation in APP/PS1 transgenic mice models with Alzheimers disease(AD), and to explore the possible mechanism. Methods The effects of ICA on learning, memory and spatial cognitive abilities of mice were examined with Morris water maze test. The effects of ICA on the deposition of β-amyloid protein(Aβ), activation of glial cells and generation of proinflammatory cytokines in the hippocampus of mice were detected with immunohistochemical staining. The expression changes of proteins related to NF-κB inflammatory signal response pathway were determined with Western blotting. Results (1) ICA reduced the escape latency(F_{4th day}=4.96, P=0.017; F_{5th day}=9.37, P=0.001)and increased the time in the target section(F=9.31, P=0.001). (2) ICA reduced the deposition of Aβ in the hippocampus of APP/PS1 mice(F_{Aβ area}=153.28, P<0.001; F_{Aβ IOD}=87.18, P<0.001). (3) ICA inhibited the expression of neurone maker GFAP and Iba-1(F_GFAP=370.16, P<0.001; F_Iba-1=32.11, P<0.001)and the generation of proinflammatory cytokine IL-1β(F=190.10, P<0.001). (4) ICA decreased the ratio of NF-κ B pathway protein p-p65/p65(F=338.77, P<0.001). Conclusion Long-term icariin treatment can improve the cognitive function of APP/PS1 mice by inhibiting the activation of glial cells, reducing the generation of proinflammatory cytokines and Aβ deposition in the hippocampus.

Key words: Alzheimers disease, Icariin, β-amyloid protein, APP/PS1 transgenic mice, Neuroinflammation

中图分类号:

R749.16

王冉冉,朱天瑞,张凤,王敏,闵傲雪,李恒,李晓红. 长期淫羊藿苷治疗对APP/PS1小鼠神经炎症的影响[J]. 山东大学学报 (医学版), 2020, 58(4): 71-77.

WANG Ranran, ZHU Tianrui, ZHANG Feng, WANG Min, MIN Aoxue, LI Heng, LI Xiaohong. Effects of long-term icariin treatment on neuroinflammation in APP/PS1 mice[J]. Journal of Shandong University (Health Sciences), 2020, 58(4): 71-77.

参考文献

[1] Frost GR, Jonas LA, Li YM. Friend, foe or both? immune activity in Alzheimers disease [J]. Front Aging Neurosci, 2019, 11: 337. doi: 10.3389/fnagi.2019.00337.
[2] Rajendran L, Paolicelli RC. Microglia-mediated synapse loss in Alzheimers disease [J]. Neuro Sci, 2018, 38(12): 2911-2919.
[3] Tublin JM, Adelstein JM, Del Monte F, et al. Getting to the heart of Alzheimer disease [J]. Circ Res, 2019,124(1):142-149.
[4] Griciuc A, Patel S, Federico AN, et al. TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer's disease [J]. Neuron, 2019, 1039(5): 820-835.
[5] Van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-beta-independent regulators of tau pathology in Alzheimer disease [J]. Nat Rev Neurosci, 2020, 21(1): 21-35.
[6] Sarlus H, Heneka MT. Microglia in Alzheimers disease [J]. J Clin Invest, 2017, 127(9): 3240-3249.
[7] Wu B, Feng JY, Yu LM, et al. Icariin protects cardiomyocytes against ischaemia/reperfusion injury by attenuating sirtuin 1-dependent mitochondrial oxidative damage [J]. Br J Pharmacol, 2018,175(21): 4137-4153.
[8] Niculescu AB, Le-Niculescu H, Roseberry K, et al. Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs [J]. Mol Psychiatry, 2019. doi: 10.1038/s41380-019-0602-2.
[9] Zhang L, Shen C, Chu J, et al. Icariin decreases the expression of APP and BACE-1 and reduces the β-amyloid burden in an APP transgenic mouse model of Alzheimers disease [J]. Int J Biol Sci, 2014, 10(2): 181-191.
[10] Zhu T, Zhang F, Li H, et al. Long-term icariin treatment ameliorates cognitive deficits via CD4+T cell-mediated immuno-inflammatory responses in APP/PS1 mice [J]. Clin Interv Aging, 2019, 14: 817-826. doi: 10.2147/CIA.S208068.
[11] Wang Y, Zhu T, Wang M, et al. Icariin attenuates M1 activation of microglia and Aβ plaque accumulation in the hippocampus and prefrontal Cortex by up-regulating PPARγ in restraint/isolation-stressed APP/PS1 mice [J]. Front Neuro Sci, 2019, 13: 291. doi: 10.3389/fnins.2019.00291.
[12] Lopez-Picon FR, Snellman A, Eskola O, et al. Neuroinflammation appears early on PET imaging and then plateaus in a mouse model of Alzheimer disease [J]. J Nucl Med, 2018, 59(3): 509-515.
[13] Joshi G, Gan KA, Johnson DA, et al. Increased Alzheimer's disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy [J]. Neuro Biol Aging, 2015, 36(2): 664-679.
[14] Jin WS, Shen LL, Bu XL, et al. Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model [J]. Acta Neuro Pathol, 2017, 134(2): 207-220.
[15] Li F, Zhang Y, Lu X, et al. Icariin improves the cognitive function of APP/PS1 mice via suppressing endoplasmic reticulum stress [J]. Life Sci, 2019, 234: 116739. doi: 10.1016/j.lfs.2019.116739.
[16] Finneran DJ, Nash KR. Neuroinflammation and fractalkine signaling in Alzheimers disease [J]. J Neuroinflammation, 2019, 16(1): 30.
[17] Hemonnot AL, Hua J, Ulmann L, et al. Microglia in Alzheimer disease: well-known targets and new opportunities [J]. Front Aging Neurosci, 2019, 11: 233. doi10.3389/fnagi.2019.00233.
[18] Ulland TK, Colonna M. TREM2-a key player in microglial biology and Alzheimer disease [J]. Nat Rev Neurol, 2018,14(11): 667-675.
[19] 方力群, 王亚楠, 高红梅, 等. 姜黄素对阿尔茨海默病模型小鼠脑内胶质细胞介导的炎症反应的抑制作用[J]. 国际神经病学神经外科学杂志, 2017, 44(4): 347-351. FANG Liqun, WANG Yanan, GAO Hongmei, et al. Inhibitory effect of curcumin on glial cell-mediated inflammation in a mouse model of Alzheimers disease [J]. Journal of International Neurology and Neurosurgery, 2017, 44(4): 347-351.
[20] Zhang YY, Fan YC, Wang M, et al. Atorvastatin attenuates the production of IL-1β, IL-6, and TNF-α in the hippocampus of an amyloid β1-42-induced rat model of Alzheimers disease [J]. Clin Interv Aging, 2013, 8: 103-110. doi: 10.2147/CIA.S40405.
[21] Liu J, Liu L, Sun J, et al. Icariin protects hippocampal neurons from endoplasmic reticulum stress and NF-κB mediated apoptosis in fetal rat hippocampal neurons and asthma rats [J]. Front Pharmacol, 2020, 10: 1660. doi: 10.3389/fphar.2019.01660.
[22] Seo EJ, Fischer N, Efferth T. Phytochemicals as inhibitors of NF-κB for treatment of Alzheimers disease [J]. Pharmacol Res, 2018, 129: 262-273. doi: 10.1016/j.phrs.2017.11.030.
[23] Ham HJ, Han JH, Lee YS, et al. Bee venom soluble phospholipase A2 exerts neuroprotective effects in a lipopolysaccharide-induced mouse model of Alzheimers disease via inhibition of nuclear factor-kappa B [J]. Front Aging Neurosci, 2019, 11: 287. doi: 10.3389/fnagi.2019.00287.
[24] 刘昌雄, 黄雄杰, 肖湘君, 等. 淫羊藿苷对大鼠皮瓣缺血再灌注损伤后炎症反应的抑制作用[J]. 中国临床药理学杂志, 2019, 35(6): 532-535. LIU Changxiong, HUANG Xiongjie, XIAO Xiangjun, et al. Inhibits effect of icariin on the inflammatory response after ischemia-reperfusion injury of rat skin flap [J]. The Chinese Journal of Clinical Pharmacology, 2019, 35(6): 532-535.
[25] Mi B, Wang J, Liu Y, et al. Icariin activates autophagy via down-regulation of the NF-κB signaling-mediated apoptosis in chondrocytes [J]. Front Pharmacol, 2018, 9: 605. doi: 10.3389/fphar.2018.00605.
[26] Tejera D, Mercan D, Sanchez-Caro JM, et al. Systemic inflammation impairs microglial Aβclearance through NLRP3 inflammasome [J]. EMBO J, 2019, 38(17): e101064. doi: 10.15252/embj.2018101064

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