氯化锂对APP/PS1双转基因小鼠脑组织中β淀粉样蛋白含量的影响
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摘要
目的:探究氯化锂(LiCl)对APP/PS1双转基因小鼠脑组织中β-淀粉样肽(Aβ)含量的影响。方法:用PCR及琼脂糖电泳方法分选4月及8月龄野生型及APP/PS1双转基因小鼠,将小鼠分为野生型(WT)组、WT+Li组、APP/PS1组及APP/PS1+Li组4组(n=6),WT+Li组和APP/PS1+Li组小鼠采用LiCl灌胃2个月[100 mg/(kg·d)], WT组及APP/PS1组采用等量生理盐水灌胃处理(试验检测时4组小鼠为6月及10月龄);采用免疫组织化学法检测6月及10月龄小鼠脑组织中老年斑数量,采用ELISA法测定小鼠脑组织内不可溶性Aβ含量。结果:灌胃结束时,与WT组小鼠比较,APP/PS1双转基因小鼠脑组织内老年斑数量、不可溶性Aβ含量均显著升高(P<0.05),10月龄小鼠更明显;与APP/PS1组小鼠比较,APP/PS1+Li组小鼠脑组织内老年斑数量及不可溶性Aβ含量显著降低,差异有统计学意义(P<0.05)。结论:LiCl可减少APP/PS1双转基因小鼠脑组织Aβ含量,这可能是其治疗精神性疾病的机制之一。
Objective: To investigate the effect of lithium chloride(LiCl) on the content of β-amyloid peptide(Aβ) in the brains of APP/PS1 double transgenic mice. Methods: Wild-type(WT) and APP/PS1 double transgenic mice at 4 and 8 months old were verified by genotyping. Experimental groups included WT group, WT+Li group, APP/PS1 group and APP/PS1+Li group. WT+Li group and APP/PS1+Li group were intragastrically administered with 100 mg/(kg·d) LiCl for 2 months, while WT group and APP/The PS1 group was treated with the same amount of normal saline. Senile plaques in the brain tissues of mice at 6 and 10 months old were detected by immunohistochemistry. The content of insoluble Aβ in mouse brain tissue was determined by ELISA. Results: At the end of the treatment,, the numbers of senile plaques and insoluble Aβ in APP/PS1 double transgenic mice were significantly increased when compared with WT group(P<0.05). Senile plaques and insoluble Aβ were more obvious in 10 months-old mice. Compared with APP/PS1 group, the number of senile plaques and the content of insoluble Aβ were significantly decreased in the brains of APP/PS1+Li group(P<0.05). Conclusion: LiCl treatment can reduce the Aβ content in brain tissue of APP/PS1 double transgenic mice. It may be one of the mechanisms used in clinical treatment of mental diseases.
Objective: To investigate the effect of lithium chloride(LiCl) on the content of β-amyloid peptide(Aβ) in the brains of APP/PS1 double transgenic mice. Methods: Wild-type(WT) and APP/PS1 double transgenic mice at 4 and 8 months old were verified by genotyping. Experimental groups included WT group, WT+Li group, APP/PS1 group and APP/PS1+Li group. WT+Li group and APP/PS1+Li group were intragastrically administered with 100 mg/(kg·d) LiCl for 2 months, while WT group and APP/The PS1 group was treated with the same amount of normal saline. Senile plaques in the brain tissues of mice at 6 and 10 months old were detected by immunohistochemistry. The content of insoluble Aβ in mouse brain tissue was determined by ELISA. Results: At the end of the treatment,, the numbers of senile plaques and insoluble Aβ in APP/PS1 double transgenic mice were significantly increased when compared with WT group(P<0.05). Senile plaques and insoluble Aβ were more obvious in 10 months-old mice. Compared with APP/PS1 group, the number of senile plaques and the content of insoluble Aβ were significantly decreased in the brains of APP/PS1+Li group(P<0.05). Conclusion: LiCl treatment can reduce the Aβ content in brain tissue of APP/PS1 double transgenic mice. It may be one of the mechanisms used in clinical treatment of mental diseases.
引文
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[22]袁玉婷,佀营营,王占洋,等.LiCl对冈田酸所致SK-N-SH神经元突触萎缩的保护作用[J].中国药理学通报,2016,32(5):670-675.
[23]CISTERNAS P,ZOLEZZI J M,MARTINEZ M,et al.Wnt-induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease[J].J Neurochem,2019,149(1):54-72.
[24]PAN Y,SHORT J L,NEWMAN S A,et al.Cognitive benefits of Lithium chloride in APP/PS1 mice are associated with enhanced brain clearance of β-amyloid[J].Brain BehavImmun,2018,70:36-47.
[2] 张贺奡,庆宏.阿尔茨海默症发病机制及治疗方法研究进展[J].科技导报,2017,35(10):52-63.
[3] PANZA F,LOZUPONE M,SERIPA D,et al.Amyloid-β immunotherapy for Alzheimer disease:is it now a long shot[J].Ann Neurol,2019,85(3):303-315.
[4] HARDY J,SELKOE D J.The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J].Sci,2002,297:353-356.
[5] BEYREUTHER K,MASTERS C L.Amyloid precursor protein (APP) and A4 amyloid in the etiology of Alzheimer’s disease:precursor-product relationships in the derangement of neuronal function[J].Brain Pathol,1991,1:241-251.
[6] YANG L B,LINDHOLM K,YAN R,et al.Elevated-secretase expression and enzymatic activity detected in sporadic Alzheimer disease[J].Nat Med,2003,9:3-4.
[7] PENKE B,BOGAR F,FULOP L.β-Amyloid and the pathomechanisms of Alzheimer’s disease:a comprehensive view[J].Molecules,2017,22:58-69.
[8] GUPTA J,FATIMA M T,ISLAM Z,et al.Nanoparticle formulations in the diagnosis and therapy of Alzheimer's disease[J] .Int J Biol Macromol,2019,130:515-526.
[9] 沈其杰.锂治疗心境障碍的50年回顾[J].中华精神科杂志,2004,37(1):1-3.
[10]陈华,季建林.锂盐在精神疾病中的应用[J].上海医药,2014,(19):9-12.
[11]王淑敏,陈林林,王伟,等.LiCl通过抑制GSK-3β的活性防治AD的研究[J].中国医学前沿杂志,2014,6(7):17-19.
[12]ENGEL T,GONI-OLIVER P,LUCAS J J,et al.Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation,but pre-formed neurofibrillary tangles do not revert[J].J Neurochem,2006,99(6):1445-1455.
[13]XIONG Y S,WANG D L,TAN L,et al.Inhibition of glycogen synthase kinase-3β reverses tau hyperphosphorylation induced by Pin1 down-regulation[J].CNS Neurol Disord Drug Targets,2013,12(3):436-443.
[14]赵蕾.吡咯喹啉醌三锂干预阿尔茨海默病的实验研究[D].上海:复旦大学,2013.
[15]PIKE C J,BURDICK D,WALENCEWICZ A J,et al.Neurodegeneration induced by beta-amyloid peptides in vitro:the role of peptide assembly state[J].The Journal of Neuroscience,1993,13(4):1676-1687.
[16]YANG T,LI S,XU H,et al.Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate[J].J Neurosci,2017,37:152-163.
[17]CHOI S H,KIM Y H,HEBISCH M,et al.A three-dimensional human neural cell culture model of Alzheimer's disease[J].Nature,2014,515(7526):274-278.
[18]SHANKAR G M ,LI S ,MEHTA T H ,et al.Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory[J].Nature Medicine,2008,14(8):837-842.
[19]FINNIE G S,GUNNARSSON R,MANAVIS J,et al.Characterization of an 'amyloid only' transgenic (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax) mouse model of Alzheimer's disease[J] .J Comp Pathol,2017,156:389-399.
[20]BILOTTA F,EVERED L A,GRUENBAUM S E.Neurotoxicity of anesthetic drugs:an update[J] .Curr Opin Anaesthesiol,2017,30:452-457.
[21]KERR F,BJEDOY I,SOFOLA-ADESAKIN O.Molecular mechanisms of Lithium action:switching the light on multiple targets for dementia using animal models[J].Front Mol Neurosci,2018,11:297-303.
[22]袁玉婷,佀营营,王占洋,等.LiCl对冈田酸所致SK-N-SH神经元突触萎缩的保护作用[J].中国药理学通报,2016,32(5):670-675.
[23]CISTERNAS P,ZOLEZZI J M,MARTINEZ M,et al.Wnt-induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease[J].J Neurochem,2019,149(1):54-72.
[24]PAN Y,SHORT J L,NEWMAN S A,et al.Cognitive benefits of Lithium chloride in APP/PS1 mice are associated with enhanced brain clearance of β-amyloid[J].Brain BehavImmun,2018,70:36-47.
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