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]. 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]. 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] 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]. 中华脑科疾病与康复杂志(电子版), 2023, 13(03): 156-161.
[2] 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]. 中华脑科疾病与康复杂志(电子版), 2022, 12(03): 157-161.
[3] 中国医师协会神经内科医师分会, 阿尔茨海默病药物临床试验写作组. 阿尔茨海默病药物临床试验中国专家共识[J]. 中华脑科疾病与康复杂志(电子版), 2022, 12(01): 9-20.
[4] 徐如祥, 杨超, 陈强, 张洪钿. 间充质干细胞治疗阿尔茨海默病的现状与展望[J]. 中华脑科疾病与康复杂志(电子版), 2020, 10(01): 1-5.
[5] 李嘉辰, 刘献增. 经颅磁刺激在阿尔茨海默病诊断及治疗中的研究进展[J]. 中华临床医师杂志(电子版), 2021, 15(04): 308-312.
[6] 许韵晨, 王憭瑶, 裴建. ApoE基因多态性与阿尔茨海默病中医证候的相关性探讨[J]. 中华针灸电子杂志, 2020, 09(04): 142-145.
[7] 刘倩, 李鑫, 刘欣, 苑金香. 铁死亡在阿尔茨海默病发病机制中的研究进展[J]. 中华诊断学电子杂志, 2022, 10(03): 211-215.
[8] 乔蕾, 孙寅轶, 曲忠森. tau蛋白和β-淀粉样蛋白在阿尔茨海默病病理过程中作用及自噬机制的研究概况[J]. 中华诊断学电子杂志, 2019, 07(02): 94-97.
[9] 徐玉振, 王茜, 单敏, 王涛, 杨位霞, 张新萍. 高压氧治疗对阿尔茨海默病患者认知功能及血清Humanin水平的影响[J]. 中华诊断学电子杂志, 2019, 07(02): 83-86.
[10] 孙寅轶, 王姝瑾, 刘帮健, 曲忠森. 2型糖尿病并发阿尔茨海默病患者外周血淋巴细胞蛋白磷酸酯酶-2A的变化[J]. 中华诊断学电子杂志, 2019, 07(02): 78-82.
[11] 胡华, 吴永华. 睡眠障碍与阿尔茨海默病[J]. 中华老年病研究电子杂志, 2020, 07(03): 41-47.
[12] 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]. 中华脑血管病杂志(电子版), 2023, 17(04): 404-409.
[13] 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]. 中华脑血管病杂志(电子版), 2023, 17(03): 290-293.
[14] 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]. 中华脑血管病杂志(电子版), 2022, 16(05): 351-355.
[15] 周英奕, 时晶, 魏明清, 倪敬年, 李婷, 张立苹, 谭中建, 田金洲. 基于动脉自旋磁共振技术探讨阿尔茨海默病脑血流特点与认知功能的关系[J]. 中华脑血管病杂志(电子版), 2021, 15(05): 302-307.
阅读次数
全文


摘要