RNSP改善APP/PS1小鼠海马线粒体质量与学习记忆能力的研究
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摘要
为探讨藏药七十味珍珠丸(ratanasampil,RNSP)对阿尔茨海默症(Alzheimer’s disease, AD)病理中海马线粒体融合、分裂及学习记忆能力的影响,以APP/PS1小鼠为实验对象,利用Morris水迷宫、RT-PCR、透射电镜、ELISA等实验手段,对小鼠的空间学习记忆能力,线粒体融合、分裂,线粒体形态结构及功能的关键指标进行了系统检测。结果表明:持续给药RNSP 12周,可改善APP/PS1小鼠空间学习记忆能力,上调APP/PS1小鼠海马线粒体融合相关基因即线粒体融合蛋白(mitofusin1/2, mfn1,mfn2)基因和视神经萎缩症蛋白质1(optic atrophy protein1,Opa1)基因的mRNA,下调线粒体分裂基因动力相关蛋白质1(dynamin-related protein 1,Drp1)基因的mRNA,改善线粒体形态结构,上调海马ATP合成酶基因(ATP Synthetase C)的mRNA及ATP水平。结果提示,RNSP改善APP/PS1小鼠学习记忆能力的机制,可能与RNSP对该模型小鼠海马线粒体融合、分裂及后续能量代谢的改善有关。
In order to investigate the effect of Tibetan medicine ratanasampil(RNSP) on the hippocampal mitochondrial fusion, fission and the ability of learning and memory in Alzheimer′s disease(AD), APP/PS1 mice were used as experimental subjects in. The spatial learning and memory ability of the APP/PS1 mice, the mitochondrial fusion and fission, the mitochondrial morphology and function of the mice were tested respectively by means of Morris water maze, RT-PCR, transmission electron microscopy, ELISA and so on. The results showed that continuous administration of RNSP for 12 weeks could improve the spatial learning and memory ability of APP/PS1 mice, up-regulate the expression of mitochondrial fusion genes mfn1, Mfn2 and Opa1 in the hippocampus of APP/PS1 mice, down-regulate the expression of mitochondrial fission gene Drp1, improve the morphological structure of mitochondria, and up-regulate the expression of ATP Synthetase C and ATP level in the hippocampus. It is suggested that the mechanism of RNSP improving the learning and memory abilities of APP/PS1 mice may be related to the improvement of mitochondrial fusion, fission and subsequent energy metabolism in hippocampus of APP/PS1 mice induced by RNSP.
In order to investigate the effect of Tibetan medicine ratanasampil(RNSP) on the hippocampal mitochondrial fusion, fission and the ability of learning and memory in Alzheimer′s disease(AD), APP/PS1 mice were used as experimental subjects in. The spatial learning and memory ability of the APP/PS1 mice, the mitochondrial fusion and fission, the mitochondrial morphology and function of the mice were tested respectively by means of Morris water maze, RT-PCR, transmission electron microscopy, ELISA and so on. The results showed that continuous administration of RNSP for 12 weeks could improve the spatial learning and memory ability of APP/PS1 mice, up-regulate the expression of mitochondrial fusion genes mfn1, Mfn2 and Opa1 in the hippocampus of APP/PS1 mice, down-regulate the expression of mitochondrial fission gene Drp1, improve the morphological structure of mitochondria, and up-regulate the expression of ATP Synthetase C and ATP level in the hippocampus. It is suggested that the mechanism of RNSP improving the learning and memory abilities of APP/PS1 mice may be related to the improvement of mitochondrial fusion, fission and subsequent energy metabolism in hippocampus of APP/PS1 mice induced by RNSP.
引文
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[2] MANCZAK M,CALKINS M J,REDDY P H.Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer′s disease:implications for neuronal damage[J].Human Molecular Genetics,2011,20(13):2495-2509.
[3] MANCZAK M,REDDY P H.Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer′s disease neurons:implications for mitochondrial dysfunction and neuronal damage[J].Human Molecular Genetics,2012,21(11):2538-2547.
[4] QI X,QVIT N,SU Y C,et al.A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity[J].Journal of Cell Science,2013,126(3):789-802.
[5] XIE N,WANG C,LIAN Y,et al.Inhibition of mitochondrial fission attenuates Abeta-induced microglia apoptosis[J].Neuroscience,2014,256:36-42.
[6] CHEN H,MCCAFFERY J M,CHAN D C.Mitochondrial fusion protects against neurodegeneration in the cerebellum[J].Cell,2007,130(3):548-562.
[7] 闫清伟,色里玛,巴桑次仁,等.藏药七十味珍珠丸改善APP/PS1小鼠学习记忆能力[J].中国生物化学与分子生物学报,2017(12):1251-1257.
[8] 廉婷,孔光耀,高氦,等.棕色田鼠和小鼠的空间学习记忆能力及AVP效应的比较[J].陕西师范大学学报(自然科学版),2012,40(2):57-61.
[9] 刘陶,郁婧,钱召强,等.两种睡眠剥夺模型对小鼠情绪和学习记忆的影响[J].陕西师范大学学报(自然科学版),2018,46(5):77-82.
[10] SILVA D F,SELFRIDGE J E,LU J,et al.Mitochondrial abnormalities in Alzheimer's disease:possible targets for therapeutic intervention[J].Advances in Pharmacology,2012,64:83-126.
[11] 贾振伟.哺乳动物线粒体质量控制的机制[J].中国细胞生物学学报,2017,39(3):373-380.
[12] PALMER C S,OSELLAME L D,LAINE D,et al.MiD49 and MiD51,new components of the mitochondrial fission machinery[J].Embo Reports,2011,12(6):565-573.
[13] 张玉森,董瑞瑞,杨倩,等.阿尔兹海默病中线粒体损伤机制及多酚对其防治的研究进展[J].现代预防医学,2017,44(13):2411-2414.
[14] KANG S,MOON N R,KIM D S,et al.Central acylated ghrelin improves memory function and hippocampal AMPK activation and partly reverses the impairment of energy and glucose metabolism in rats infused with beta-amyloid[J].Peptides,2015,71:84-93.
[15] PEI L,MU Y,LEBLANC M,et al.Dependence of hippocampal function on ERRgamma-regulated mitochondrial metabolism[J].Cell Metabolism,2015,21(4):628-636.
[16] XIA C,ZHU L,SHAO W,et al.The Effect of hippocampal cognitive impairment and XIAP on glucose and lipids metabolism in rats[J].Cellular Physiology and Biochemistry,2016,38(2):609-618.
[17] HUANG T T,LEU D,ZOU Y.Oxidative stress and redox regulation on hippocampal-dependent cognitive functions[J].Archives of Biochemistry and Biophysics,2015,576:2-7.
[18] HERNANDEZ-ZIMBRON L F,RIVAS-ARANCIBIA S.Oxidative stress caused by ozone exposure induces beta-amyloid 1-42 overproduction and mitochondrial accumulation by activating the amyloidogenic pathway[J].Neuroscience,2015,304:340-348.
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