中国医科大学学报

中国医科大学学报
  • 中文核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
  • BA、CA收录

中国医科大学学报 ›› 2018, Vol. 47 ›› Issue (3): 193-197.doi: 10.12007/j.issn.0258-4646.2018.03.001

• 论著 •    下一篇

DMT1在APP/PS1转基因小鼠小脑皮质中表达上调

王思亓1, 李欣潞2, 林庚2, 王卓2,3, 程晓凤2, 刘彤彤2,4, 郑玮2   

  1. 1. 中国医科大学临床一系, 沈阳 110122;
    2. 中国医科大学基础医学院组织学与胚胎学教研室, 沈阳 110122;
    3. 锦州医科大学护理学院妇儿护理学教研室, 辽宁 锦州 121001;
    4. 辽宁省人民医院神经内科, 沈阳 110016
  • 收稿日期:2017-09-28 出版日期:2018-03-30 发布日期:2018-03-24
  • 通讯作者: 郑玮 E-mail:wzheng@cmu.edu.cn
  • 作者简介:王思亓(1996-),女,本科在读.
  • 基金资助:
    国家自然科学基金(81471112);辽宁省自然科学基金(2014021033)

Elevation of Divalent Metal Transporter 1 Protein in the Cerebellar Cortex of the APP/PS1 Transgenic Mouse

WANG Siqi1, LI Xinlu2, LIN Geng2, WANG Zhuo2,3, CHENG Xiaofeng2, LIU Tongtong2,4, ZHENG Wei2   

  1. 1. The 1st Clinical Department, China Medical University, Shenyang 110122, China;
    2. Department of Histology and Embryology, College of Basic Medical Science, China Medical University, Shenyang 110122, China;
    3. Department of Pediatric Nursing, College of Nursing, Jinzhou Medical University, Jinzhou 121001, China;
    4. Department of Neurology, The People's Hospital of Liaoning Province, Shenyang 110016, China
  • Received:2017-09-28 Online:2018-03-30 Published:2018-03-24

摘要: 目的 研究二价金属离子转运体1(DMT1)在APP/PS1转基因小鼠小脑内的分布。方法 应用免疫组织化学、免疫荧光双标染色和共聚焦激光扫描显微镜观察DMT1和β-淀粉样蛋白(Aβ)在APP/PS1转基因小鼠小脑老年斑内的定位和分布,应用Western blotting检测DMT1在APP/PS1转基因小鼠小脑内的蛋白表达水平。结果 DMT1和Aβ免疫阳性产物均定位于老年斑内,分子层内较多,而浦肯野细胞层和颗粒层较少。与野生型小鼠相比,DMT1蛋白表达水平在APP/PS1转基因小鼠小脑内显著升高。结论 APP/PS1转基因小鼠小脑Aβ老年斑内有大量DMT1表达,提示DMT1及其参与转运的二价金属离子可能参与小脑Aβ老年斑形成。

关键词: 二价金属离子转运体1, β-淀粉样蛋白, APP/PS1转基因小鼠, 小脑, 阿尔茨海默病

Abstract: Objective To investigate the distribution of divalent metal transporter 1 (DMT1) in the cerebellum of APP/PS1 transgenic mouse. Methods Immunohistochemistry,immunofluorescence,and confocal laser scanning microscopy were used to analyze the relationship between DMT1 and amyloid beta (Aβ) and their distribution in senile plaques. Western blotting was used to analyze DMT1 protein level in the APP/PS1 transgenic mouse cerebellum. Results DMT1 and Aβ were mainly located in the amyloid plaques,which were predominately located in the molecular layer of the cerebellar cortex of the transgenic mouse. Only a few plaques could be seen in the Purkinje cell layer and granular layer. Confocal laser microscopy revealed the DMT1 and Aβ were co-localized in senile plaques. Conclusion The abundant expression of DMT1 protein suggests that DMT1 and the divalent metal ions that it transports might be involved in the formation of Aβ senile plaques and other pathological processes in the cerebellum in Alzheimer's disease.

Key words: divalent metal transporter 1, amyloid beta, APP/PS1 transgenic mouse, cerebellum, Alzheimer's disease

中图分类号: 

  • R322.81
[1] WANG P,WANG ZY. Metal ions influx is a double edged sword for the pathogenesis of Alzheimer's disease[J]. Aging Res Rev,2017,35:265-290. DOI:10.1016/j.arr.2016.10.003.
[2] ROBERTS BR,RYAN TM,BUSH AI,et al. The role of metallobiology and amyloid-beta peptides in Alzheimer's disease[J]. J Neurochem,2012,120(Suppl 1):149-166. DOI:10.1111/j.1471-4159.2011.07500.x.
[3] KE Y,CHANG YZ,DUAN XL,et al. Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain[J]. Neurobiol Aging,2005,26(5):739-748. DOI:10.1016/j.neurobiolaging.2004.06.002.
[4] SALAZAR J,MENA N,HUNOT S,et al. Divalent metal transporter 1(DMT1) contributes to neurodegeneration in animal models of Parkinson's disease[J]. Proc Natl Acad Sci USA,2008,105(47):18578-18583. DOI:10.1073/pnas.0804373105.
[5] ZHANG S,WANG J,SONG N,et al. Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP (+))-induced apoptosis in MES23.5 cells[J]. Neurobiol Aging,2009,30(9):1466-1476. DOI:10.1016/j.neurobiolaging.2007.11.025.
[6] HUANG E,ONG WY,GO ML,CONNOR JR. Upregulation of iron regulatory proteins and divalent metal transporter-1 isoforms in the rat hippocampus after kainate induced neuronal injury[J]. Exp Brain Res,2006,170(3):376-386. DOI:10.1007/s00221-005-0220-x.
[7] ZHANG CW,TAI YK,CHAI BH,et al. Transgenic mice overexpressing the divalent metal transporter 1 exhibit iron accumulation and enhanced Parkin expression in the brain[J]. Neuromolecular Med,2017,19(2/3):375-386. DOI:10.1007/s12017-017-8451-0.
[8] ZHENG W,XIN N,CHI ZH,et al. Divalent metal transporter 1 is involved in amyloid precursor protein processing and Abeta generation[J]. FASEB J,2009,23(12):4207-4217. DOI:10.1096/fj.09-135749.
[9] KOBAYASHI K,FUKUTANI Y,HAYASHI M,et al. Non-familial olivopontocerebellar atrophy combined with late onset Alzheimer's disease:a clinico-pathological case report[J]. J Neurol Sci,1998,154(1):106-112. DOI:10.1016/S0022-510X (97) 00209-8.
[10] OLAJIDE OJ,UGBOSANMI AT,ENAIBE BU,et al. Cerebellar molecular and cellular characterization in rat models of Alzheimer's disease:neuroprotective mechanisms of garcinia biflavonoid complex[J]. Ann Neurosci,2017,24(1):32-45. DOI:10.1159/000464421.
[11] CATAFAU AM,BULLICH S,SEIBYL JP,et al. Cerebellar amyloid-β plaques:how frequent are they,and do they influence 18F-florbetaben SUV ratios?[J]. J Nucl Med,2016,57(11):1740-1745. DOI:10.2967/jnumed.115.171652.
[12] MANN DM,SINCLAIR KG. The quantitative assessment of lipofuscin pigment,cytoplasmic RNA and nucleolar volume in senile dementia[J]. Neuropathol Appl Neurobiol,1978,4(2):129-135. DOI:10.1111/j.1365-2990.1978.tb00553.x.
[13] SJBECK M,ENGLUND E. Alzheimer's disease and the cerebellum:a morphologic study on neuronal and glial changes[J]. Dement Geriatr Cogn Disord,2001,12(3):211-218. DOI:10.1159/000051260.
[14] MATTIACE LA,DAVIES P,YEN SH,et al. Microglia in cerebellar plaques in Alzheimer's disease[J]. Acta Neuropathol,1990,80(5):493-498.
[15] LEMERE CA,LOPERA F,KOSIK KS,et al. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology[J]. Nat Med,1996,2(10):1146-1150.
[16] WANG HY,D'ANDREA MR,NAGELE RG. Cerebellar diffuse amyloid plaques are derived from dendritic Abeta42 accumulations in Purkinje cells[J]. Neurobiol Aging,2002,23(2):213-223. DOI:10.1016/S0197-4580(01) 00279-2.
[17] LYUBARTSEVA G,SMITH JL,MARKESBERY WR,et al. Alterations of zinc transporter proteins ZnT-1,ZnT-4 and ZnT-6 in preclinical Alzheimer's disease brain[J]. Brain Pathol,2010,20(2):343-350. DOI:10.1111/j.1750-3639.2009.00283.x.
[18] ZHENG W,WANG T,YU D,et al. Elevation of zinc transporter ZnT3 protein in the cerebellar cortex of the AbetaPP/PS1 transgenic mouse[J]. J Alzheimers Dis,2010,20(1):323-331. DOI:10.3233/JAD-2010-136.
[19] GONZLEZ-DOMNGUEZ R,GARCA-BARRERA T,GMEZ-ARIZA JL. Homeostasis of metals in the progression of Alzheimer's disease[J]. Biometals,2014,27(3):539-549. DOI:10.1007/s10534-014-9728-5.
[20] DONG J,ATWOOD CS,ANDERSON VE,et al. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores:Raman microscopic evidence[J]. Biochemistry,2003,42(10):2768-2773. DOI:10.1021/bi0272151.
[21] SAYRE LM,PERRY G,HARRIS PL,et al. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease:a central role for bound transition metals[J]. J Neurochem,2000,74(1):270-279. DOI:10.1046/j.1471-4159.2000.0740270.x.
[22] SUH SW,JENSEN KB,JENSEN MS,et al. Histochemically-reactive zinc in amyloid plaques,angiopathy,and degenerating neurons of Alzheimer's diseased brains[J]. Brain Res,2000,852(2):274-278. DOI:10.1016/S0006-8993(99) 02096-X.
[23] LEE JY,MOOK-JUNG I,KOH JY. Histochemically reactive zinc in plaques of the Swedish mutant beta-amyloid precursor protein transgenic mice[J]. J Neurosci,1999,19(11):RC10.
[24] CHEIGNON C,TOMAS M,BONNEFONT-ROUSSELOT D,et al. Oxidative stress and the amyloid beta peptide in Alzheimer's disease[J]. Redox Biol,2018,14:450-464. DOI:10.1016/j.redox.2017.10.014.
[25] VEUTHEY T,WESSLING-RESNICK M. Pathophysiology of the Belgrade rat[J]. Front Pharmacol,2014,22(5):82. DOI:10.3389/fphar.2014.00082.
[26] BURDO JR,SIMPSON IA,MENZIES S,et al. Regulation of the profile of iron-management proteins in brain microvasculature[J]. J Cereb Blood Flow Metab,2004,24(1):67-74. DOI:10.1097/01.WCB.0000095800.98378.03.
[27] BURDO JR,MENZIES SL,SIMPSON IA,et al. Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat[J]. J Neurosci Res,2001,66(6):1198-1207. DOI:10.1002/jnr.1256.
[28] GUNSHIN H,MACKENZIE B,BERGER UV,et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter[J]. Nature. 1997,388(6641):482-488. DOI:10.1038/41343.
[29] KNUTSON M,MENZIES S,CONNOR J,et al. Developmental,regional,and cellular expression of SFT/UbcH5A and DMT1 mRNA in brain[J]. J Neurosci Res,2004,76(5):633-641. DOI:10.1002/jnr.20113.
[1] 王海英, 李慧源, 罗红月, 张慧予, 姜扬, 郭利晴, 陶蕾, 孙晓红. 青蒿素调控NF-κB信号通路介导阿尔茨海默病炎症反应细胞模型的研究[J]. 中国医科大学学报, 2018, 47(6): 552-555,561.
[2] 张利华, 张丽艳, 张小康, 徐超龙, 周义. β-淀粉样蛋白诱导的阿尔茨海默病大鼠模型中BDNF与TRPC3的关系[J]. 中国医科大学学报, 2018, 47(3): 217-221.
[3] 张改改,张丽艳,邹丹,沈薇,金戈,张利华. 经典瞬时受体电位通道蛋白在 β 淀粉样蛋白诱导的阿尔茨海默病 小鼠海马区的表达[J]. 中国医科大学学报, 2016, 45(12): 1100-1104.
[4] 康笑,隋汝波,张磊,马贺骥. 小脑-下丘脑通路在卒中后抑郁发病机制中的作用[J]. 中国医科大学学报, 2015, 44(5): 389-393.
[5] 丛琳,张楠楠,佡剑非,任艳. 甲基化芯片检测APP/PS1双转基因小鼠基因组DNA甲基化分布[J]. 中国医科大学学报, 2015, 44(2): 160-163.
[6] 费洪新,韩玉生,杜徽,姜波,李宝龙,朴成玉,张英博,仲丽丽,白云,周忠光. 补阳还五汤对APP/PS1双转基因小鼠学习记忆及海马组织白介素?6水平的影响[J]. 中国医科大学学报, 2014, 43(8): 677-681.
[7] 李刚,解丽梅,赵丹,次旦旺久,张晓雯,孟新月. VCI-C与MRI观察胎儿小脑蚓部、小脑幕形态的对比研究[J]. 中国医科大学学报, 2013, 42(12): 1137-1140.
[8] 董红丽,李颖,周志可,张荣伟,张惠敏. 急性小脑梗死31例临床分析[J]. 中国医科大学学报, 2012, 41(8): 762-765.
[9] 赵彬,商秀丽 ,何志义,范国光,刘虎. 阿尔茨海默病的静息态fMRI低频振幅研究[J]. 中国医科大学学报, 2012, 41(4): 329-332.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!

中国医科大学学报版权所有©2018

未经允许,严禁擅自转载本站图文资料

地址:中国 沈阳市沈北新区蒲河路77号 110122

辽ICP备05014850

JOURNAL OF CHINA MEDICAL UNIVERSITY

ADDRESS: NO.77 PUHE ROAD

SHENYANG NORTH NEW AREA, SHENYANG

LIAONING PROVINCE, P.R. CHINA