神经节苷脂GM1对Aβ_(1-42)诱导的AD小鼠学习记忆能力及神经细胞凋亡的影响
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摘要
目的考察鹿茸中单唾液酸四己糖神经节苷脂(monosialotetrahexosylganglioside,GM1)对Aβ_(1-42)诱导的阿尔茨海默症(alzheimer’s disease,AD)小鼠病理模型的学习记忆能力以及淀粉样前体蛋白(amyloid precursor protein,APP)、淀粉样蛋白(Aβ)、细胞凋亡的影响。方法实验动物随机分成6组,每组8只。侧脑室注射Aβ_(1-42)制备AD模型,采用GM1腹腔给药,应用自主活动检测小鼠运动能力,应用水迷宫、Y迷宫、新物体识别实验检测小鼠空间记忆及学习能力,应用试剂盒检测APP、 Aβ、半胱氨酸天冬氨酸蛋白水解酶-3(caspase-3)以及半胱氨酸天冬氨酸蛋白水解酶-9(caspase-9)水平。结果 GM1给药组与模型组相比,GM1小鼠Y迷宫的自发交替率增加,水迷宫的逃避潜伏期逐渐变短;并且降低APP、Aβ、caspase-3、caspase-9的积累。结论 GM1能明显改善AD小鼠学习记忆能力,其机制可能与降低APP、Aβ水平以及抑制神经细胞凋亡有关。
Objective To investigate the effect of monosialotetrahexosylganglioside(GM1)on learning and memory ability and APP,Aβ and apoptosis in Aβ_(1-42)-induced dementia mice model.Methods Mice were randomly divided into six groups,with 8 mice in each group.Intracerebroventricular injection of amyloid(Aβ)to prepare dementia model,with intraperitoneal administration of GM1,the athletic ability of mice was detected by autonomous activity,the spatial memory and learning ability of mice were measured by Morris water maze test,Y maze test and new object recognition experiment.The levels of amyloid precursor protein(APP),Aβ_(1-42),cysteine aspartic proteolytic enzyme-3(Caspase-3)and cysteine aspartate protease-9(Caspase-9)were measured with ELISA.Results Compared with the model group,the spontaneous alternation rate of the Y maze of GM1 mice increased,the escape latency of water maze was shorter,and the accumulation of APP,Aβ,Caspase-3 and Caspase-9 was decreased.Conclusion GM1 can significantly improve the learning and memory ability of AD mice,the mechanism may be related to reducing the level of APP,Aβ and inhibition of neuronal apoptosis.
Objective To investigate the effect of monosialotetrahexosylganglioside(GM1)on learning and memory ability and APP,Aβ and apoptosis in Aβ_(1-42)-induced dementia mice model.Methods Mice were randomly divided into six groups,with 8 mice in each group.Intracerebroventricular injection of amyloid(Aβ)to prepare dementia model,with intraperitoneal administration of GM1,the athletic ability of mice was detected by autonomous activity,the spatial memory and learning ability of mice were measured by Morris water maze test,Y maze test and new object recognition experiment.The levels of amyloid precursor protein(APP),Aβ_(1-42),cysteine aspartic proteolytic enzyme-3(Caspase-3)and cysteine aspartate protease-9(Caspase-9)were measured with ELISA.Results Compared with the model group,the spontaneous alternation rate of the Y maze of GM1 mice increased,the escape latency of water maze was shorter,and the accumulation of APP,Aβ,Caspase-3 and Caspase-9 was decreased.Conclusion GM1 can significantly improve the learning and memory ability of AD mice,the mechanism may be related to reducing the level of APP,Aβ and inhibition of neuronal apoptosis.
引文
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[2] KHODARAHMI R,ASHRAFI-KOOSHK M R.Is there correlation between Abeta-heme peroxidase activity and the peptide aggregation state?A literature review combined with hypothesis[J].Int J Biol Macromol,2017,100:18-36.
[3] BLENNOW K,MATTSSON N,SCHOLL M,et al.Amyloid biomarkers in Alzheimer′s disease[J].Trends Pharmacol Sci,2015,36(5):297-309.
[4] 李明秋,黄海华,张国胜,等.神经节苷脂治疗阿尔茨海默病的疗效和安全性观察[J].实用医学杂志,2012(05):804-806.
[5] WANG X,TAO S Y,CONG P X,et al.Neuroprotection of strongylocentrotus nudus gangliosides against alzheimer’s disease via regulation of neurite loss and mitochondrial apoptosis[J].Journal of Functional Foods,2017,33:122-133.
[6] COPENHAVER P F K,GEL D.Role of APP Interactions with heterotrimeric G proteins:Physiological functions and pathological consequences[J].Frontiers in Molecular Neuroscience,2017:10.
[7] KIM D I,KIM J S,CHANG W C,et al.Abeta-induced drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis[J].Biochim Biophys Acta,2016,1863(11):2820-2834.
[8] CAVALLUCCI V,D′AMELIO M,CECCONI F.Abeta toxicity in alzheimer′s disease[J].Mol Neurobiol,2012,45(2):366-378.
[9] COPENHAVER P F,KOGEL D.Role of APP interactions with heterotrimeric G proteins:Physiological functions and pathological consequences[J].Front Mol Neurosci,2017:103.
[10] AMIT T,BAR-AM O,MECHLOVICH D,et al.The novel multitarget iron chelating and propargylamine drug M30 affects APP regulation and processing activities in alzheimer′s disease models[J].Neuropharmacology,2017,123:359-367.
[11] 宋修云,胡金凤,陈乃宏.神经细胞凋亡与脑缺血疾病[J].中国药理学通报,2012,03:307-310.
[12] YANG T T,HSU C T,KUO Y M.Cell-derived soluble oligomers of human amyloid-beta peptides disturb cellular homeostasis and induce apoptosis in primary hippocampal neurons[J].J Neural Transm(Vienna),2009,116(12):1561-1569.
[13] DONG Y.RNA interference-mediated silencing of BACE and APP attenuates the isoflurane-induced caspase activation[J].Medical Gas Research,2011,1(1):5.