外周血单核细胞中组织蛋白酶表达与阿尔茨海默病发展的相关性研究
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摘要
目的探讨外周血免疫细胞中溶酶体酶与阿尔茨海默病(Alzheimers disease,AD)病程发展的关系。方法选择2012年1月~2017年12月于中国医科大学附属第一医院及附属盛京医院神经内科、老年病科以及体检中心就诊年龄≥60岁的AD、轻度认知障碍(MCI)患者及健康老年人共78例,其中AD组30例,MCI组28例,健康老年人为对照组20例。采用实时定量PCR方法检查各组Cathepsin B、Cathepsin D mRNA表达水平,并检查Cathepsin B、Cathepsin D活性,采用ELISA方法检测单核细胞内β淀粉样蛋白(Aβ1-42)水平。结果AD组Cathepsin B、Cathepsin D mRNA表达水平及活性明显低于对照组和MCI组,单核细胞内Aβ1-42水平明显高于对照组和MCI组,差异有统计学意义(P<0.01,P<0.05)。MCI组单核细胞Cathepsin B、Cathepsin D mRNA表达水平及活性、以及单核细胞内Aβ1-42水平与对照组比较均无统计学差异(P>0.05)。结论外周血单核细胞Cathepsin B、Cathepsin D表达及活性下调可以作为AD病程发展阶段的评价指标,AD患者外周血单核细胞对于Aβ的降解能力下降与Cathepsin B、Cathepsin D表达下调有关,Cathepsin B、Cathepsin D在MCI组表达下调的意义需增加样本量进一步随访研究。
Objective To study the relationship between expression of cathepsin in peripheral blood monocytes and progression of Alzheimer's disease(AD).Methods Seventy-eight≥60 years old subjects admitted to our hospital for the treatment of AD and mild cognitive impairment(MCI)or physical examination were divided into AD group(n=30),MCI group(n=28)and control group(n=20).Expression and activity of cathepsin B and cathepsin D mRNA in 3 groups were detected by RT-PCR and serum Aβ1-42 level in monocytes was measured by ELISA.Results The expression level and activity of cathepsin B and cathepsin D mRNA were significantly lower and the serum level of Aβ1-42 in monocytes was significant higher in AD group than in control group and MCI group(P<0.01,P<0.05).No significant difference was found in expression level and activity of cathepsin B and cathepsin D mRNA and serum level of Aβ1-42 in monocytes between MCI group and control group(P>0.05).Conclusion The downregulated expression level and activity of cathepsin B and cathepsin D mRNA can be used as a predictor of AD progression.Peripheral blood monocytes are related with the reduced deposition of Aβand the downregulated expression of cathepsin B and cathepsin D.
Objective To study the relationship between expression of cathepsin in peripheral blood monocytes and progression of Alzheimer's disease(AD).Methods Seventy-eight≥60 years old subjects admitted to our hospital for the treatment of AD and mild cognitive impairment(MCI)or physical examination were divided into AD group(n=30),MCI group(n=28)and control group(n=20).Expression and activity of cathepsin B and cathepsin D mRNA in 3 groups were detected by RT-PCR and serum Aβ1-42 level in monocytes was measured by ELISA.Results The expression level and activity of cathepsin B and cathepsin D mRNA were significantly lower and the serum level of Aβ1-42 in monocytes was significant higher in AD group than in control group and MCI group(P<0.01,P<0.05).No significant difference was found in expression level and activity of cathepsin B and cathepsin D mRNA and serum level of Aβ1-42 in monocytes between MCI group and control group(P>0.05).Conclusion The downregulated expression level and activity of cathepsin B and cathepsin D mRNA can be used as a predictor of AD progression.Peripheral blood monocytes are related with the reduced deposition of Aβand the downregulated expression of cathepsin B and cathepsin D.
引文
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[3]Zuroff L,Daley D,Black KL,et al.Clearance of cerebral Aβin Alzheimer's disease:reassessing the role of microglia and monocytes[J].Cell Mol Life Sci,2017,74(12):2167-2201.DOI:10.1007/s00018-017-2463-7.
[4]Khan TK,Alkon DL.Peripheral biomarkers of Alzheimer's disease[J].J Alzheimers Dis,2015,44(3):729-744.DOI:10.3233/JAD-142262.
[5]Mammana S,Fagone P,Cavalli E,et al.The role of macrophages in neuroinflammatory and neurodegenerative pathways of Alzheimer's disease,amyotrophic lateral sclerosis,and multiple sclerosis:pathogenetic cellular effectors and potential therapeutic targets[J].Int J Mol Sci,2018,19(3):E831.DOI:10.3390/ijms19030831.
[6]Solé-Domènech S,Rojas AV,Maisuradze GG,et al.Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar Aβby multiple endoproteolytic cleavages within theβ-sheet domain[J].Proc Natl Acad Sci U S A,2018,115(7):1493-1498.DOI:10.1073/pnas.1719808115.
[7]Thériault P,ElAli A,Rivest S.The dynamics of monocytes and microglia in Alzheimer's disease[J].Alzheimers Res Ther,2015,7(1):41.DOI:10.1186/s13195-015-0125-2.
[8]Goetzl EJ,Boxer A,Schwartz JB,et al.Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease[J].Neurology,2015,85(1):40-47.DOI:10.1212/WNL.0000000000001702.
[9]田力,冯娟,石权,等.阿尔茨海默病患者外周血单核细胞的疾病相关基因筛查[J].中华老年医学杂志,2016,35(12):1267-1270.DOI:10.3760/cma.j.issn.0254-9026.2016.12.003.
[10]Tian L,Zhang K,Tian ZY,et al.Decreased expression of cathepsin D in monocytes is related to the defective degradation of amyloid-βin Alzheimer's disease[J].J Alzheimers Dis,2014,42(2):511-520.DOI:10.3233/JAD-132192.
[11]Perez SE,He B,Nadeem M,et al.Hippocampal endosomal,lysosomal,and autophagic dysregulation in mild cognitive impairment:correlation with Aβand tau pathology[J].J Neuropathol Exp Neurol,2015,74(4):345-358.DOI:10.1097/NEN.0000000000000179.
[12]Xu W,Fang F,Ding J,et al.Dysregulation of Rab5-mediated endocytic pathways in Alzheimer's disease[J].Traffic,2018,19(4):253-262.DOI:10.1111/tra.12547.
[13]Perlenfein TJ,Murphy RM.A mechanistic model to predict effects of cathepsin B and cystatin C onβ-amyloid aggregation and degradation[J].J Biol Chem,2017,292(51):21071-21082.DOI:10.1074/jbc.M117.811448.
[14]Moors T,Paciotti S,Chiasserini D,et al.Lysosomal dysfunction andα-synuclein aggregation in Parkinson's disease:diagnostic links[J].Mov Disord,2016,31(6):791-801.DOI:10.1002/mds.26562.
[15]Ji XR,Cheng KC,Chen YR,et al.Dysfunction of different cellular degradation pathways contributes to specificβ-amyloid42-induced pathologies[J].FASEB J,2018,32(3):1375-1387.DOI:10.1096/fj.201700199RR.