阿尔茨海默病发病机制及药物治疗研究进展
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摘要
阿尔茨海默病(Alzheimer Disease,AD)是一种病因及发病机制尚未完全阐明的神经退行性疾病,其表现为记忆力下降和日常行为能力的丧失、认知障碍和人格改变。有关其发病机制众说纷纭,包括与微环境相关的Aβ-淀粉样肽级联假说、胆碱能损伤学说、免疫异常学说等,与神经元相关的Tau蛋白假说、神经细胞凋亡学说等,与基因相关的载脂蛋白ε4基因、早老素1和早老素2基因、淀粉样前体蛋白基因等;其药物治疗有西药治疗,包括乙酰胆碱酯酶抑制剂、减少β-淀粉样蛋白(Aβ)的产生、沉积药物、抗氧化剂等;中药治疗,包括补虚类药物、活血化瘀药、化痰平喘药等。本文就几年来国内外AD病的发病机制和治疗药物的研究进展进行综述。
Alzheimer's disease( Alzheimer disease,AD) is a neurodegenerative disease of which etiology and pathogenesis has not been fully elucidated. Its symptoms are decreased memory and daily behavior capacity loss,cognitive impairment and personality changes. The pathogenesis are divergent,including micro environment related A beta amyloid cascade hypothesis,cholinergic damage theory,the abnormal immune theory,associated with neuronal Tau protein hypothesis,neural cell apoptosis theory,genes associated with apolipoprotein epsilon 4 gene,presenilin 1 and presenilin 2 gene and amyloid precursor protein gene. The western medicine treatment includes acetylcholinesterase inhibitor,reduced beta amyloid( A beta) generation,drug deposition,antioxidants and others. The traditional Chinese medicine treatment includes tonic drugs,living blood stasis drugs,eliminating phlegm and relieving asthma drugs. This article reviews the research progress of the pathogenesis and drug treatment of AD in recent years at home and abroad.
Alzheimer's disease( Alzheimer disease,AD) is a neurodegenerative disease of which etiology and pathogenesis has not been fully elucidated. Its symptoms are decreased memory and daily behavior capacity loss,cognitive impairment and personality changes. The pathogenesis are divergent,including micro environment related A beta amyloid cascade hypothesis,cholinergic damage theory,the abnormal immune theory,associated with neuronal Tau protein hypothesis,neural cell apoptosis theory,genes associated with apolipoprotein epsilon 4 gene,presenilin 1 and presenilin 2 gene and amyloid precursor protein gene. The western medicine treatment includes acetylcholinesterase inhibitor,reduced beta amyloid( A beta) generation,drug deposition,antioxidants and others. The traditional Chinese medicine treatment includes tonic drugs,living blood stasis drugs,eliminating phlegm and relieving asthma drugs. This article reviews the research progress of the pathogenesis and drug treatment of AD in recent years at home and abroad.
引文
[1]Prince M,Wimo A,Guerche M,et al.World Alzheimer Report 2015-The global impact of dementia:an analysis of prevalence,incidence,cost and trends[J].Alzheimer's Disease International,2015,7:1-5.
[2]Alzheimer's Association Report.Alzheimer's disease facts and figures Alzheimer's Association”[J].Alzheimer's&Dementia,2015,11:332-384.
[3]Henriques AG,Oliveira JM,Gomes B,et al.Complexing Aβprevents the cellular anomalies induced by the Peptide alone[J].J Mol Neurosci,2014,53(4):661-668.
[4]Shankar G M,Li S,Mehta T H,et al.Amyloid-betaprotein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory[J].Nat Med,2008,14(8):837-842.
[5]Laferla F M,Tinkle B T,Bieberich C J,et al.The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice[J].Nat Genet,1995,9(1):21-30.
[6]Small DH.Dysregulation of Ca2+homeostasis in Alzheimer's disease:role in acetylcholinesterase production and AMPA receptor internalization[J].Neuro degenerative Dis,2012,10:76-79.
[7]董贤慧,柴锡庆.阿尔茨海默病转基因动物模型:如何更接近病理特征?[J].中国组织工程研究,2013,17(46):8075-8082.
[8]Kannan M1,Manivel P,Geetha K,et al.Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene(NMSM)derivatives against Alzheimer disease:to understand their interacting mechanism with acetylcholinesterase[J].Journal of Chemical Biology,2012,5(4):151-166.
[9]Ikonomovic MD,Abrahamson EE,Isanski BA,et al.Superior frontal cor-tex cholinergic axon density in mild cognitive impairment and early Alzheimer disease[J].Arch Neurol,2007,64(9):1312-1317.
[10]Zheng H,Youdim MB,Fridkin M.Selective acetylcholinesterase inhibitor activated by acetylcholinesterase releases an active chelator with neurorescuing and anti-amyloid activities[J].ACS Chemical Neuroscience,2010,1(11):737-746.
[11]Mc Geer PL,Rogers J,Mc Geer EC.Neuroimmunemechanisms in Alzheimer disease pathog-enesis[J].Alzheimer Dis Assoc Discord,1994,8(3):149-158.
[12]马英,曹云鹏.阿尔茨海默病的神经免疫炎症发病机制及其治疗研究进展[J].中国老年学杂志,2010,30(21):3200-3204.
[13]Joshi P,Turola E,Ruiz A,et al.Microglia convert aggregated amyloid-βinto neurotoxic forms through the shedding of microvesicles[J].Cell Death and Differentiation,2014,21:582-593.
[14]Alex E.Roher,David H.Cribbs,Ronald C.Kim,et al.Bapineuzumab Alters AβComposition:Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy[J].PLOS One,2013,8(3):e59735.
[15]Brawek B1,Garaschuk O.Network-wide dysregulation of calcium homeostasis in Alzheimer's disease[J].Cell and Tissue Research,2014,357(2):427-438.
[16]陈茜茜,苏涛.微循环在阿尔茨海默病发生发展中的作用[J].生物化学与生物物理进展,2015,41(12):1077-1083.
[17]Bolognin S,Messori L,Drago D,et al.Copper,iron and zinc differentially alter amyloid-Aβ(1-42)aggregation and toxicity[J].The International Journal of Biochemistry&Cell Biology,2011,43(6):877-885.
[18]Butterfield DA,Di Domenico F,Barone E.Elevated risk of type 2 diabetes for development of Alzheimer disease:a key role for oxidative stress in brain[J].Biochimica et Biophysica Acta(BBA)-Molecular Basis of Disease,2014,1842(9):1693-1706.
[19]许保磊,王蓉.兴奋性氨基酸转运体2在神经退行性变中的作用[J].中国比较医学杂志,2012,22(10):67-71.
[20]Do TD,Economou NJ,Chamas A,et al.Interactions between Amyloid-βand Tau Fragments Promote Aberrant Aggregates:Implications for Amyloid Toxicity[J].J Phys Chem B,2014,118(38):11220-11230.
[21]CATALDO A M,PETERHOFF C M,TRONCOSO J C,et al.Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Downsyndrome:Differential effects of APOE genotype and presenilin mutations[J].Am J Pathol,2000,157(3):277-286.
[22]Sanjay W,Pimplikar.Reassessing the amyloid cascade hypothesis of Alzheim er's disease[J].The International Journalof Biochemis-try&Cell Biology,2009,41:1261-1268.
[23]董雯,郑爽.阿尔茨海默病病因及发病机制的研究[J].中国老年保健医学,2011,9(1):37-39.
[24]EdgünlüTG,Ozge A,Yaln O,et al.A Study of the Impact of Death Receptor 4(DR4)Gene Polymorphisms in Alzheimer's Disease[J].Balkan Med J,2013,30(3):268-272.
[25]Yagi R,Miyamoto R,Morino H,et al.Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing[J].Neurobiology of Aging,2014,35(7):1780.e1-1780.e5.
[26]庄莹,陈杰.阿尔茨海默病病因及发病机制研究进展[J].吉林医药学院学报,2008,29(2):101-103.
[27]Ting SK,Chong MS,Kandiah N,et al.Absence of A673T amyloid-βprecursor protein variant in Alzheimer's disease and other neurological diseases[J].Neurobiology of Aging,2013,34(10):2441.e7-2441.e8.
[28]Bozzali M,Parker GJ,SpanòB,et al.Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease[J].Human Brain Mapping,2013,34(12):3158-3167.
[29]Sano M,Ernesto C,Thomas RG,et al.A controlled trial of selegiline,alpha-tocopherol,or both as treatment for Alzheimer's disease.The Alzheimer's Disease Cooperative Study[J].N Engl J Med,1997,336(17):1216-1222.
[30]徐学君,徐德琴,汪骏.多奈哌齐的药理作用及其临床应用研究进展[J].安徽医药,2009,13(4):352-354.
[31]Menting KW,Claassen JA.β-secretase inhibitor;a promising novel therapeutic drug in Alzheimer's disease[J].Front Aging Neurosci,2014,6:165.
[32]Dysken MW,Sano M,Asthana S,et al.Effect of vitamin E and memantine on functional decline in Alzheimer disease:the TEAM-AD VA cooperative randomized trial[J].JAMA.2014,311(1):33-44.
[33]Peters O.Alzheimer's disease:are non-steroidal anti-inflammatory drugs effective?[J].Dtsch Med Wochenschr,2012,137(50):2627.
[34]王澎伟.雌激素在阿尔茨海默病中神经保护作用的研究进展[J].医学综述,2013,19(17):3095-3097.
[35]王珏,于恩彦.雌激素对阿尔茨海默病认知功能改善的研究进展[J].神经疾病与精神卫生,2013,13(5):523-526.
[36]郑爽,董雯,冯志强.阿尔茨海默病的治疗现状[J].老年保健医学,2011,9(1):42-45.
[37]孟烨,张庆林.防治阿尔茨海默病的中药活性成分研究进展[J].生物技术通讯,2015,26(4):587-590.
[38]黎巍威,王学美.中医从“肾”防治阿尔茨海默病的现代研究[J].中国实验方剂学杂志,2010,16(13):227-231.
[39]闫敬来,陈燕清.治疗老年痴呆常用中药归经和功效归类分析研究[J].中国中医急症,2008,17(3):340-343.
[40]杜仕静.中药成分影响阿尔茨海默病β-淀粉样蛋白靶点的研究进展[J].中草药,2015,46(13):1989-1995.
[41]刘婷婷,顾婷,葛雅南.骨碎补总黄酮的富集工艺及其对Aβ-(25-35)诱导PC12损伤细胞保护作用研究[J].黑龙江科技信息,2017,20(3):166-167.
[42]韦云,刘美霞,梁晓东,等.还脑益聪方提取物含药血清对APP/PS1双基因转染细胞γ分泌酶活性及相关蛋白表达的影响[J].中国药理学通报,2017,33(3):417-426.
[43]张旭彤,王孝庆,王中苏,等.姜黄素抑制β淀粉样蛋白致小胶质瘤细胞神经炎性反应[J].温州医科大学学报,2017,47(2):85-89.
[44]曲岩,王佳志,李文鹏,等.补阳还五汤中有效成分对AD细胞模型的影响的实验研究[J].湖北中医药大学学报,2017,19(1):11-15.
[45]刘娜,王金华,王华龙,等.红景天对老年痴呆大鼠认知功能的治疗作用[J].河北医科大学学报,2017,38(2):133-137.
[46]杨德森,干国平,李浩浩,等.红景天苷对阿尔茨海默病模型大鼠学习记忆能力和海马组织Aβ含量及p75NTR表达的影响[J].医药导报,2017,36(2):141-144.
[47]郑博闻,姜招峰,黄汉昌.姜黄素抑制Cu2+诱导的转APP_(695)基因SH-SY5Y细胞氧化损伤和凋亡作用[J].食品科学,2017,38(3):164-169.
[48]杨坦.肉桂改善阿尔茨海默病大鼠学习记忆通过抑制海马氧化应激[J].中医临床研究,2017,9(2):8-11.
[49]肖弯,曹晓璐,张容,等.黄芩苷改善Aβ_(25-35)诱导的小鼠学习和记忆障碍及可能机制[J].中国药理学与毒理学杂志,2017,31(1):59-64.
[50]艾亮.参芪五味子片对阿尔茨海默小鼠的治疗作用及其对小鼠血清与海马体氧化应激水平的影响[J].实用药物与临床,2017,20(1):15-19.
[2]Alzheimer's Association Report.Alzheimer's disease facts and figures Alzheimer's Association”[J].Alzheimer's&Dementia,2015,11:332-384.
[3]Henriques AG,Oliveira JM,Gomes B,et al.Complexing Aβprevents the cellular anomalies induced by the Peptide alone[J].J Mol Neurosci,2014,53(4):661-668.
[4]Shankar G M,Li S,Mehta T H,et al.Amyloid-betaprotein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory[J].Nat Med,2008,14(8):837-842.
[5]Laferla F M,Tinkle B T,Bieberich C J,et al.The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice[J].Nat Genet,1995,9(1):21-30.
[6]Small DH.Dysregulation of Ca2+homeostasis in Alzheimer's disease:role in acetylcholinesterase production and AMPA receptor internalization[J].Neuro degenerative Dis,2012,10:76-79.
[7]董贤慧,柴锡庆.阿尔茨海默病转基因动物模型:如何更接近病理特征?[J].中国组织工程研究,2013,17(46):8075-8082.
[8]Kannan M1,Manivel P,Geetha K,et al.Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene(NMSM)derivatives against Alzheimer disease:to understand their interacting mechanism with acetylcholinesterase[J].Journal of Chemical Biology,2012,5(4):151-166.
[9]Ikonomovic MD,Abrahamson EE,Isanski BA,et al.Superior frontal cor-tex cholinergic axon density in mild cognitive impairment and early Alzheimer disease[J].Arch Neurol,2007,64(9):1312-1317.
[10]Zheng H,Youdim MB,Fridkin M.Selective acetylcholinesterase inhibitor activated by acetylcholinesterase releases an active chelator with neurorescuing and anti-amyloid activities[J].ACS Chemical Neuroscience,2010,1(11):737-746.
[11]Mc Geer PL,Rogers J,Mc Geer EC.Neuroimmunemechanisms in Alzheimer disease pathog-enesis[J].Alzheimer Dis Assoc Discord,1994,8(3):149-158.
[12]马英,曹云鹏.阿尔茨海默病的神经免疫炎症发病机制及其治疗研究进展[J].中国老年学杂志,2010,30(21):3200-3204.
[13]Joshi P,Turola E,Ruiz A,et al.Microglia convert aggregated amyloid-βinto neurotoxic forms through the shedding of microvesicles[J].Cell Death and Differentiation,2014,21:582-593.
[14]Alex E.Roher,David H.Cribbs,Ronald C.Kim,et al.Bapineuzumab Alters AβComposition:Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy[J].PLOS One,2013,8(3):e59735.
[15]Brawek B1,Garaschuk O.Network-wide dysregulation of calcium homeostasis in Alzheimer's disease[J].Cell and Tissue Research,2014,357(2):427-438.
[16]陈茜茜,苏涛.微循环在阿尔茨海默病发生发展中的作用[J].生物化学与生物物理进展,2015,41(12):1077-1083.
[17]Bolognin S,Messori L,Drago D,et al.Copper,iron and zinc differentially alter amyloid-Aβ(1-42)aggregation and toxicity[J].The International Journal of Biochemistry&Cell Biology,2011,43(6):877-885.
[18]Butterfield DA,Di Domenico F,Barone E.Elevated risk of type 2 diabetes for development of Alzheimer disease:a key role for oxidative stress in brain[J].Biochimica et Biophysica Acta(BBA)-Molecular Basis of Disease,2014,1842(9):1693-1706.
[19]许保磊,王蓉.兴奋性氨基酸转运体2在神经退行性变中的作用[J].中国比较医学杂志,2012,22(10):67-71.
[20]Do TD,Economou NJ,Chamas A,et al.Interactions between Amyloid-βand Tau Fragments Promote Aberrant Aggregates:Implications for Amyloid Toxicity[J].J Phys Chem B,2014,118(38):11220-11230.
[21]CATALDO A M,PETERHOFF C M,TRONCOSO J C,et al.Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Downsyndrome:Differential effects of APOE genotype and presenilin mutations[J].Am J Pathol,2000,157(3):277-286.
[22]Sanjay W,Pimplikar.Reassessing the amyloid cascade hypothesis of Alzheim er's disease[J].The International Journalof Biochemis-try&Cell Biology,2009,41:1261-1268.
[23]董雯,郑爽.阿尔茨海默病病因及发病机制的研究[J].中国老年保健医学,2011,9(1):37-39.
[24]EdgünlüTG,Ozge A,Yaln O,et al.A Study of the Impact of Death Receptor 4(DR4)Gene Polymorphisms in Alzheimer's Disease[J].Balkan Med J,2013,30(3):268-272.
[25]Yagi R,Miyamoto R,Morino H,et al.Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing[J].Neurobiology of Aging,2014,35(7):1780.e1-1780.e5.
[26]庄莹,陈杰.阿尔茨海默病病因及发病机制研究进展[J].吉林医药学院学报,2008,29(2):101-103.
[27]Ting SK,Chong MS,Kandiah N,et al.Absence of A673T amyloid-βprecursor protein variant in Alzheimer's disease and other neurological diseases[J].Neurobiology of Aging,2013,34(10):2441.e7-2441.e8.
[28]Bozzali M,Parker GJ,SpanòB,et al.Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease[J].Human Brain Mapping,2013,34(12):3158-3167.
[29]Sano M,Ernesto C,Thomas RG,et al.A controlled trial of selegiline,alpha-tocopherol,or both as treatment for Alzheimer's disease.The Alzheimer's Disease Cooperative Study[J].N Engl J Med,1997,336(17):1216-1222.
[30]徐学君,徐德琴,汪骏.多奈哌齐的药理作用及其临床应用研究进展[J].安徽医药,2009,13(4):352-354.
[31]Menting KW,Claassen JA.β-secretase inhibitor;a promising novel therapeutic drug in Alzheimer's disease[J].Front Aging Neurosci,2014,6:165.
[32]Dysken MW,Sano M,Asthana S,et al.Effect of vitamin E and memantine on functional decline in Alzheimer disease:the TEAM-AD VA cooperative randomized trial[J].JAMA.2014,311(1):33-44.
[33]Peters O.Alzheimer's disease:are non-steroidal anti-inflammatory drugs effective?[J].Dtsch Med Wochenschr,2012,137(50):2627.
[34]王澎伟.雌激素在阿尔茨海默病中神经保护作用的研究进展[J].医学综述,2013,19(17):3095-3097.
[35]王珏,于恩彦.雌激素对阿尔茨海默病认知功能改善的研究进展[J].神经疾病与精神卫生,2013,13(5):523-526.
[36]郑爽,董雯,冯志强.阿尔茨海默病的治疗现状[J].老年保健医学,2011,9(1):42-45.
[37]孟烨,张庆林.防治阿尔茨海默病的中药活性成分研究进展[J].生物技术通讯,2015,26(4):587-590.
[38]黎巍威,王学美.中医从“肾”防治阿尔茨海默病的现代研究[J].中国实验方剂学杂志,2010,16(13):227-231.
[39]闫敬来,陈燕清.治疗老年痴呆常用中药归经和功效归类分析研究[J].中国中医急症,2008,17(3):340-343.
[40]杜仕静.中药成分影响阿尔茨海默病β-淀粉样蛋白靶点的研究进展[J].中草药,2015,46(13):1989-1995.
[41]刘婷婷,顾婷,葛雅南.骨碎补总黄酮的富集工艺及其对Aβ-(25-35)诱导PC12损伤细胞保护作用研究[J].黑龙江科技信息,2017,20(3):166-167.
[42]韦云,刘美霞,梁晓东,等.还脑益聪方提取物含药血清对APP/PS1双基因转染细胞γ分泌酶活性及相关蛋白表达的影响[J].中国药理学通报,2017,33(3):417-426.
[43]张旭彤,王孝庆,王中苏,等.姜黄素抑制β淀粉样蛋白致小胶质瘤细胞神经炎性反应[J].温州医科大学学报,2017,47(2):85-89.
[44]曲岩,王佳志,李文鹏,等.补阳还五汤中有效成分对AD细胞模型的影响的实验研究[J].湖北中医药大学学报,2017,19(1):11-15.
[45]刘娜,王金华,王华龙,等.红景天对老年痴呆大鼠认知功能的治疗作用[J].河北医科大学学报,2017,38(2):133-137.
[46]杨德森,干国平,李浩浩,等.红景天苷对阿尔茨海默病模型大鼠学习记忆能力和海马组织Aβ含量及p75NTR表达的影响[J].医药导报,2017,36(2):141-144.
[47]郑博闻,姜招峰,黄汉昌.姜黄素抑制Cu2+诱导的转APP_(695)基因SH-SY5Y细胞氧化损伤和凋亡作用[J].食品科学,2017,38(3):164-169.
[48]杨坦.肉桂改善阿尔茨海默病大鼠学习记忆通过抑制海马氧化应激[J].中医临床研究,2017,9(2):8-11.
[49]肖弯,曹晓璐,张容,等.黄芩苷改善Aβ_(25-35)诱导的小鼠学习和记忆障碍及可能机制[J].中国药理学与毒理学杂志,2017,31(1):59-64.
[50]艾亮.参芪五味子片对阿尔茨海默小鼠的治疗作用及其对小鼠血清与海马体氧化应激水平的影响[J].实用药物与临床,2017,20(1):15-19.