切换至 "中华医学电子期刊资源库"

中华诊断学电子杂志 ›› 2019, Vol. 07 ›› Issue (02) : 98 -102. doi: 10.3877/cma.j.issn.2095-655X.2019.02.006

所属专题: 文献

认知功能障碍

糖原合酶激酶-3β在阿尔茨海默病发病机制及治疗中作用的研究概况
张梦阳1, 王玥2,()   
  1. 1. 100069 北京,首都医科大学
    2. 100020 首都医科大学附属北京朝阳医院神经内科
  • 收稿日期:2018-11-14 出版日期:2019-05-26
  • 通信作者: 王玥

Research situation on the role of glycogen synthase kinase-3β in the pathogenesis and treatment of Alzheimer′s disease

Mengyang Zhang1, Yue Wang2,()   

  1. 1. Clinical College, Capital Medical University, Beijing 100069, China
    2. Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
  • Received:2018-11-14 Published:2019-05-26
  • Corresponding author: Yue Wang
  • About author:
    Corresponding author: Wang Yue, Email:
引用本文:

张梦阳, 王玥. 糖原合酶激酶-3β在阿尔茨海默病发病机制及治疗中作用的研究概况[J/OL]. 中华诊断学电子杂志, 2019, 07(02): 98-102.

Mengyang Zhang, Yue Wang. Research situation on the role of glycogen synthase kinase-3β in the pathogenesis and treatment of Alzheimer′s disease[J/OL]. Chinese Journal of Diagnostics(Electronic Edition), 2019, 07(02): 98-102.

阿尔茨海默病(AD)是最常见的,与年龄相关的老年性痴呆症,其主要病理组织学标志是老年斑和神经元纤维缠结。糖原合成激酶-3β(GSK-3β)是糖原合成的限速酶,其功能失调会影响神经元的多种生理活动,尤其与老年斑和神经元纤维缠结形成密切相关。笔者总结了GSK-3β在AD发生和发展过程中所发挥的作用及GSK-3β抑制剂治疗AD的研究现状。

Alzheimer disease (AD) is the most common age-related senile dementia. Senile plaques and neurofibrillary tangles are two histopathological hallmarks of this disease. Glycogen synthase kinase-3β(GSK-3β) is a key enzyme in glycogen synthesis. The dysregulation of this kinase contributes to many disorders in neurophysiology, especially the formation of senile plaques and neurofibrillary tangles. In this review, we conclude the effects of GSK-3β on the development of AD and the current studies of GSK-3β inhibitors in the treatment of AD.

[1]
Glenner GG, Wong CW.Alzheimer′s disease,initial report of the purification and characterization of a novel cerebrovascular amyloid protein[J].Biochem Biophys Res Commun,1984,120(3):885-889.
[2]
Goedert M, Wischik CM, Crowther RA,et al.Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease,identification as the microtubule-associated protein tau[J].Proc Natl Acad Sci USA,1988,85(11):4051-4055.
[3]
Thornton TM, Pedraza-Alva G, Deng B,et al.Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation[J].Science,2008,320(5876):667-670.
[4]
Sharfi H, Eldar-Finkelman H.Sequential phosphorylation of insulin receptor substrate-2 by glycogen synthase kinase-3 and c-Jun NH2-terminal kinase plays a role in hepatic insulin signaling[J].Am J Physiol Endocrinol Metab,294(2):E307-E315.
[5]
O′Brien WT, Haung J, Buccafusca R,et al.Glycogen synthase kinase-3 is essential for β-arrestin-2 complex formation and lithium-sensitive behaviors in mice[J].J Clin Invest.2011,121(9):3756-3762.
[6]
Holsinger RM, McLean CA, Beyreuther K,et al.Increased expression of the amyloid precursor beta-secretase in Alzheimer′s disease[J].Ann Neurol,2002,51(6):783-786.
[7]
Cai H, Wang Y, McCarthy D,et al.BACE1 is the major beta-secretase for generation of A beta peptides by neurons[J].Nat Neurosci,2001,4(3):233-234.
[8]
Ly PT, Wu Y, Zou H,et al.Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes[J].J Clin Invest,2013,123(1):224-235.
[9]
Rezai-Zadeh K, Douglas Shytle R, Bai Y,et al.Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer′s disease beta-amyloid production[J].J Cell Mol Med,2009,13(3):574-588.
[10]
Deng Y, Xiong Z, Chen P,et al.β-amyloid impairs the regulation of N-methyl-D-aspartate receptors by glycogen synthase kinase 3[J].Neurobiol Aging,2014,35(3):449-459.
[11]
Townsend M, Mehta T, Selkoe DJ.Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway[J].J Biol Chem,2007,282(46):33305-33312.
[12]
Magdesian MH, Carvalho MM, Mendes FA,et al.Amyloid-beta binds to the extracellular cysteine-rich domain of frizzled and inhibits Wnt/beta-catenin signaling[J].J Biol Chem,2008,283(14):9359-9368.
[13]
Hui J, Zhang J, Pu M, et al. Modulation of GSK-3β/β-Catenin signaling contributes to learning and memory impairment in a rat model of depression[J].Int J Neuropsychopharmacol,2018,21(9):858-870.
[14]
Hanger DP, Noble W.Functional implications of glycogen synthase kinase-3-mediated tau phosphorylation[J].Int J Alzheimers Dis,2011(2011):352805.
[15]
Saeki K, Machida M, Kinoshita Y,et al.Glycogen synthase kinase-3β2 has lower phosphorylation activity to tau than glycogen synthase kinase-3β1[J].Biol Pharm Bull,2011,34(1):146-149.
[16]
Vossel KA, Zhang K, Brodbeck J,et al.Tau reduction prevents Abeta-induced defects in axonal transport[J].Science,2010,330(6001):198.
[17]
Vossel KA, Xu JC, Fomenko V,et al.Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β[J].J Cell Biol,2015,209(3):419-433.
[18]
Wang H, Wang R, Zhao Z,et al.Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons[J].Brain Res,2009(1249):237-243.
[19]
Wang JZ, Wang ZH.Senescence may mediate conversion of tau phosphorylation-induced apoptotic escape to neurodegeneration[J].Exp Gerontol,2015(68):82-86.
[20]
Del Pino J, Zeballos G, Anadn MJ,et al.Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade,increase in GSK-3β enzyme,β-amyloid and tau protein levels[J].Arch Toxicol,2016,90(5):1081-1092.
[21]
Samadi A, Valderas C, de los Ríos C, et al. Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases.II.Synthesis,biological assessment,and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles[J].Bioorg Med Chem,2011,19(1):122-133.
[22]
Provensi G, Costa A, Passani MB,et al.Donepezil,an acetylcholine esterase inhibitor,and ABT-239,a histamine H3 receptor antagonist/inverse agonist,require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse[J].Neuropharmacology,2016(109):139-147.
[23]
Llorens-Martin M, Lpez-Domnech G, Soriano E,et al.GSK3β is involved in the relief of mitochondria pausing in a tau-dependent manner[J].PLoS One,2011,6(11):e27686.
[24]
Llorens-Martín M, Fuster-Matanzo A, Teixeira CM,et al.GSK-3β overexpression causes reversible alterations on postsynaptic densities and dendritic morphology of hippocampal granule neurons in vivo[J].Mol Psychiatry,2013,18(4):451-460.
[25]
Buss H, Dörrie A, Schmitz ML,et al.Phosphorylation of serine 468 by GSK3β negatively regulates basal p65 NF-κB activity[J].J Biol Chem,2004,279(48):49571-49574.
[26]
Zhang H, Yang X, Qin X,et al.Caspase-3 is involved in aluminum-induced impairment of long-term potentiation in rats through the Akt/GSK-3β pathway[J].Neurotox Res,2016,29(4):484-494.
[27]
Egashira Y, Tanaka T, Soni P,et al.Involvement of the p75(NTR) signaling pathway in persistent synaptic suppression coupled with synapse elimination following repeated long-term depression induction[J].J Neurosci Res,2010,88(16):3433-3446.
[28]
Olsen KM, Sheng M.NMDA receptors and BAX are essential for Abeta impairment of LTP[J].Sci Rep,2012(2):225.
[29]
Martin M, Rehani K, Jope RS,et al.Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3[J].Nat Immunol,2005,6(8):777-784.
[30]
Fuster-Matanzo A, Llorens-Martin M, de Barreda EG,et al.Different susceptibility to neurodegeneration of dorsal and ventral hippocampal dentate gyrus:a study with transgenic mice overexpressing GSK3β[J].PLoS One,2011,6(11):e27262.
[31]
Ding Y, Qiao A, Fan GH.Indirubin-3-monoxime rescues spatial memory deficits and attenuates beta-amyloid-associated neuropathology in a mouse model of Alzheimer′s disease[J].Neurobiol Dis,2010,39(2):156-168.
[32]
Avrahami L, Farfara D, Shaham-Kol M,et al.Inhibition of glycogen synthase kinase-3 ameliorates betaamyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model:in vivo and in vitro studies[J].J Biol Chem,2013,288(2):1295-1306.
[33]
Gameiro I, Michalska P, Tenti G,et al.Discovery of the first dual GSK3βinhibitor/Nrf2 inducer.a new multitarget therapeutic strategy for Alzheimer′s disease[J].Sci Rep,2017(7):45701.
[34]
张军臣,张冉,张广宁,等.槲皮素对颞叶癫痫大鼠学习记忆能力的影响[J/CD].中华诊断学电子杂志,2016,4(2):131-135.
[35]
Jiang XY, Chen TK, Zhou JT,et al.Dual GSK-3β/AChE inhibitors as a new strategy for multitargeting anti-alzheimer′s disease drug discovery[J].ACS Med Chem Lett,2018,9(3):171-176.
[36]
何昊,关青,张浩波,等.新版轻度认知障碍临床指南概要[J/CD].中华诊断学电子杂志,2018,6(3):145-150.
[37]
Toledo EM, Inestrosa NC.Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease[J].Mol Psychiatry,2010,15(3):228,272-285.
[38]
Sudduth TL, Wilson JG, Everhart A,et al.Lithium treatment of APPSwDI/NOS2-/-mice leads to reduced hyperphosphorylated tau, increased amyloid deposition and altered inflammatory phenotype[J].PLoS ONE,2012(7):e31993.
[39]
Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment:randomised controlled trial[J].Br J Psychiatry,2011,198(5):351-356.
[40]
Pomara N.Lithium treatment in Alzheimer′s disease does not promote cognitive enhancement,but may exert long-term neuroprotective effects[J].Psychopharmacology(Berl),2009,205(1):169-170.
[41]
Huang HJ, Chen SL, Huang HY,et al.Chronic low dose of AM404 ameliorates the cognitive impairment and pathological features in hyperglycemic 3xTg-AD mice[J].Psychopharmacology (Berl),2018.[Epub ahead of print]
[42]
Rong H, Liang Y, Niu Y.Rosmarinic acid attenuates β-amyloid-induced oxidative stress via Akt/GSK-3β/Fyn-mediated Nrf2 activation in PC12 cells[J].Free Radic Biol Med,2018(120):114-123.
[43]
Paudel P, Seong SH, Zhou Y,et al.Rosmarinic acid derivatives′ inhibition of glycogen synthase kinase-3β is the pharmacological basis of kangen-karyu in alzheimer′s disease[J].Molecules,2018,23(11):E2919.
[1] 王娟, 刘晔, 熊威, 蒋财磊, 贺燕, 叶青松. 间充质干细胞缓解阿尔茨海默病氧化应激的新思路[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(02): 93-106.
[2] 王江波, 尹一鸣, 张冠群. 外周血生物标志物在阿尔茨海默病早期诊断中的价值[J/OL]. 中华脑科疾病与康复杂志(电子版), 2024, 14(04): 244-249.
[3] 李苒, 姜宇航, 陈泽浩, 何家恺, 闫珊珊, 鄢锦荣, 贾宝辉. 电针治疗阿尔茨海默病患者的先导性随机对照试验[J/OL]. 中华脑科疾病与康复杂志(电子版), 2024, 14(04): 218-224.
[4] 杨森, 阙玉梅, 丁莉, 王艺瑾, 侯庆宇. Hcy和AD7c-NTP在阿尔茨海默病诊断中的临床应用[J/OL]. 中华脑科疾病与康复杂志(电子版), 2024, 14(04): 208-212.
[5] 张萌, 喻中华. 阿尔茨海默病患者血清脂联素、Lp-PLA2、IL-17的表达及与认知功能的相关性分析[J/OL]. 中华脑科疾病与康复杂志(电子版), 2023, 13(06): 358-363.
[6] 郭翃江, 符雪彩, 朱妍妍, 严之红, 王丽娜, 纪红. 基于影响因素的老年阿尔茨海默病认知功能障碍预测模型构建及电子化认知康复训练的应用价值[J/OL]. 中华脑科疾病与康复杂志(电子版), 2023, 13(03): 156-161.
[7] 李敏, 刘云. 血清SAA、sNFL水平对老年阿尔茨海默病的预测价值分析[J/OL]. 中华脑科疾病与康复杂志(电子版), 2022, 12(03): 157-161.
[8] 于伟伟, 张国高, 吴军, 胡俊, 黄一宁, 徐晶. 线粒体相关内质网膜相关线粒体功能障碍在阿尔茨海默病中的研究进展[J/OL]. 中华临床医师杂志(电子版), 2024, 18(02): 223-230.
[9] 刘霖, 张文欢, 宋雅茹, 姜云璐. Apelin-13 在阿尔茨海默病中的神经保护作用机制研究进展[J/OL]. 中华诊断学电子杂志, 2024, 12(04): 276-280.
[10] 陆静, 钟为慧, 赵杰, 曾玲晖. 髓系细胞触发受体2在β淀粉样蛋白病理致阿尔茨海默病中的作用机制[J/OL]. 中华老年病研究电子杂志, 2024, 11(01): 51-56.
[11] 赵晓晓, 邱嘉婷, 张懿姝, 张蓉, 张棚, 刘晓蕾. 丁苯酞在各类型认知障碍治疗中的应用研究进展[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(01): 19-26.
[12] 曾德阳, 董贺千禧, 陶凉, 肖红艳, 曾燕, 鄢华. 中年心血管危险因素增加阿尔茨海默病相关痴呆的流行病学和机制研究进展[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(01): 6-13.
[13] 刘天姿, 王宝军. Toll样受体4在阿尔茨海默病中的研究进展[J/OL]. 中华脑血管病杂志(电子版), 2023, 17(04): 404-409.
[14] 夏禹, 刘寒, 朱瑞. 阿尔茨海默病及相关认知障碍疾病与早老素2基因相关性的研究进展[J/OL]. 中华脑血管病杂志(电子版), 2023, 17(03): 290-293.
[15] 宋蕾, 吴寒, 侯双兴, 楼菁菁, 刘兴党. 关于阿尔茨海默病中视网膜和视神经及相关物质的研究进展[J/OL]. 中华脑血管病杂志(电子版), 2022, 16(05): 351-355.
阅读次数
全文


摘要


AI


AI小编
你好!我是《中华医学电子期刊资源库》AI小编,有什么可以帮您的吗?