Wnt/β-catenin信号通路在阿尔茨海默病神经元变性中的研究进展
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摘要
目的:阿尔茨海默病(Alzheimer’s disease,AD)是目前老年人最常见的痴呆类型,由于AD发病机制复杂,迄今尚未完全阐明。AD最重要的神经病理学特征是β淀粉样蛋白(amyloid-βprotein,Aβ)沉积、Tau蛋白过度磷酸化形成神经纤维缠结以及脑内神经炎症反应的激活,并伴随着神经元的损伤及学习记忆功能受损。越来越多的研究指出Wnt/β-连环蛋白(Wnt/β-catenin)信号通路在神经退行性疾病中,尤其是AD中发挥了重要作用。为明确Wnt/β-catenin信号通路与AD发病、Aβ沉积、Tau蛋白和神经炎症的相关性及其机制,对相关文献进行综述。方法:选择Wnt/β-catenin信号通路与AD、Aβ神经毒性、Tau蛋白磷酸化及神经炎症相关的国内外相关文献进行综述。结果:研究表明Wnt/β-catenin信号通路参与AD的发生和发展,当该通路激活时可以抑制Aβ的沉积、Tau的过度磷酸化及神经炎症,反之则促进Aβ的产生、聚集以及Tau蛋白的磷酸化,神经炎症的发生。结论:本文就Wnt/β-catenin信号途径在AD发病中的重要性加以概述,为AD机制的研究提供了理论基础,也提示激活Wnt信号传导途径可以作为治疗AD的潜在治疗靶点。
Objective:Alzheimer's disease(AD)is the most common type of dementia in the elderly,but its pathogenesis is complex and remains unclear. The most common neuropathological features of AD include amyloid β-protein(Aβ)deposition,neurofibrillary tangles due to hyperphosphorylation of Tau protein,and the activation of brain neuroinflammation,with neuronal injury and impaired learning and memory abilities. A growing number of studies have shown that the Wnt/β-catenin signaling pathway plays an important role in neurodegenerative disorders,especially in AD. This article reviews the related literature to clarify the association of the Wnt/β-catenin signaling pathway with the pathogenesis of AD,Aβ deposition,Tau protein,and neuroinflammation and related mechanism.Methods:The articles on the association of the Wnt/β-catenin signaling pathway with AD,Aβ neurotoxicity,Tau protein phosphorylation,and neuroinflammation,published in China and foreign countries,were reviewed. Results:Studies showed that the Wnt/β-catenin signaling pathway was involved in the development and progression of AD. The activation of this pathway inhibited Aβ deposition,hyperphosphorylation of Tau protein,and neuroinflammation,and on the contrary,it promoted the formation and aggregation of Aβ,the phosphorylation of Tau protein,and the development of neuroinflammation. Conclusion:This article reviews the importance of the Wnt/β-catenin signaling pathway in the pathogenesis of AD and provides a theoretical basis for the research on the pathogenesis of AD. It is pointed out that activation of the Wnt/β-catenin signaling pathway may be used as a potential target for the treatment of AD.
Objective:Alzheimer's disease(AD)is the most common type of dementia in the elderly,but its pathogenesis is complex and remains unclear. The most common neuropathological features of AD include amyloid β-protein(Aβ)deposition,neurofibrillary tangles due to hyperphosphorylation of Tau protein,and the activation of brain neuroinflammation,with neuronal injury and impaired learning and memory abilities. A growing number of studies have shown that the Wnt/β-catenin signaling pathway plays an important role in neurodegenerative disorders,especially in AD. This article reviews the related literature to clarify the association of the Wnt/β-catenin signaling pathway with the pathogenesis of AD,Aβ deposition,Tau protein,and neuroinflammation and related mechanism.Methods:The articles on the association of the Wnt/β-catenin signaling pathway with AD,Aβ neurotoxicity,Tau protein phosphorylation,and neuroinflammation,published in China and foreign countries,were reviewed. Results:Studies showed that the Wnt/β-catenin signaling pathway was involved in the development and progression of AD. The activation of this pathway inhibited Aβ deposition,hyperphosphorylation of Tau protein,and neuroinflammation,and on the contrary,it promoted the formation and aggregation of Aβ,the phosphorylation of Tau protein,and the development of neuroinflammation. Conclusion:This article reviews the importance of the Wnt/β-catenin signaling pathway in the pathogenesis of AD and provides a theoretical basis for the research on the pathogenesis of AD. It is pointed out that activation of the Wnt/β-catenin signaling pathway may be used as a potential target for the treatment of AD.
引文
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[2]Weuve J,Hebert LE,Scherr PA,et al.Prevalence of Alzheimer disease in US states[J].Epidemiology,2015,26(1):e4-6.
[3]Scheltens P,Blennow K,Breteler MM,et al.Alzheimer’s disease[J].Lancet,2016,388(10043):505-517.
[4]Clevers H,Loh KM,Nusse R.Stem cell signaling.An integral program for tissue renewal and regeneration:Wnt signaling and stem cell control[J].Science,2014,346(6205):1248012.
[5]Veltri A,Lang C,Lien WH.Concise review:Wnt signaling pathways in skin development and epidermal stem cells[J].Stem Cells,2018,36(1):22-35.
[6]Gaesser JM,Fyffe-Maricich SL.Intracellular signaling pathway regulation of myelination and remyelination in the CNS[J].Exp Neurol,2016,283(Pt B):501-511.
[7]Inestrosa NC,Toledo EM.The role of Wnt signaling in neuronal dysfunction in Alzheimer’s disease[J].Mol Neurodegener,2008,3:9.
[8]Bilic J,Huang YL,Davidson G,et al.Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation[J].Science,2007,316(5831):1619-1622.
[9]Scali C,Caraci F,Gianfriddo M,et al.Inhibition of Wnt signaling,modulation of Tau phosphorylation and induction of neuronal cell death by DKK1[J].Neurobiol Dis,2006,24(2):254-265.
[10]Tapia-Rojas C,Inestrosa NC.Loss of canonical Wnt signaling is involved in the pathogenesis of Alzheimer’s disease[J].Neural Regen Res,2018,13(10):1705-1710.
[11]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):272-285,228.
[12]Folke J,Pakkenberg B,Brudek T.Impaired Wnt signaling in the prefrontal cortex of Alzheimer’s disease[J].Mol Neurobiol,2018[Epub ahead of print].DOI:10.1007/s12035-018-1103-z.
[13]Ghanevati M,Miller CA.Phospho-beta-catenin accumulation in Alzheimer’s disease and in aggresomes attributable to proteasome dysfunction[J].J Mol Neurosci,2005,25(1):79-94.
[14]Zhang Z,Hartmann H,Do VM,et al.Destabilization of betacatenin by mutations in presenilin-1 potentiates neuronal apoptosis[J].Nature,1998,395(6703):698-702.
[15]Rivera DS,Lindsay C,Codocedo JF,et al.Andrographolide recovers cognitive impairment in a natural model of Alzheimer’s disease(Octodon degus)[J].Neurobiol Aging,2016,46:204-220.
[16]Tapia-Rojas C,Schuller A,Lindsay CB,et al.Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3beta:autoregulation of GSK-3beta in vivo[J].Biochem J,2015,466(2):415-430.
[17]Wang CY,Zheng W,Wang T,et al.Huperzine A activates Wnt/beta-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model[J].Neuropsychopharmacology,2011,36(5):1073-1089.
[18]朱晓娟,耿排力,赵红斌,等.红景天苷通过Wnt/β-catenin信号通路影响小鼠骨髓间充质干细胞向神经元细胞定向分化[J].激光生物学报,2012,21(6):510-516.
[19]Chen F,Wang H,Xiang X,et al.Curcumin increased the differentiation rate of neurons in neural stem cells via wnt signaling in vitro study[J].J Surg Res,2014,192(2):298-304.
[20]霍江涛,张小乔,严洁,等.川芎嗪激活Wnt信号通路改善阿尔茨海默病大鼠脑组织炎性研究[J].浙江临床医学,2015,17(8):1262-1264.
[21]Portelius E,Dean RA,Andreasson U,et al.beta-site amyloid precursor protein-cleaving enzyme 1(BACE1)inhibitor treatment induces Abeta5-X peptides through alternative amyloid precursor protein cleavage[J].Alzheimers Res Ther,2014,6(5-8):75.
[22]Jha NK,Jha SK,Kumar D,et al.Impact of insulin degrading enzyme and neprilysin in Alzheimer’s disease biology:characterization of putative cognates for therapeutic applications[J].J Alzheimers Dis,2015,48(4):891-917.
[23]Tapia-Rojas C,Inestrosa NC.Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer’s disease in J20-APP transgenic and wild-type mice[J].J Neurochem,2018,144(4):443-465.
[24]Tapia-Rojas C,Aranguiz F,Varela-Nallar L,et al.Voluntary running attenuates memory loss,decreases neuropathological changes and induces neurogenesis in a mouse model of Alzheimer’s disease[J].Brain Pathol,2016,26(1):62-74.
[25]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.
[26]Liu CC,Tsai CW,Deak F,et al.Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer’s disease[J].Neuron,2014,84(1):63-77.
[27]姚宏波,廉洁,郎尉雅,等.Wnt/β-Catenin在骨髓基质干细胞治疗阿尔茨海默病大鼠脑中的表达[J].中国医药科学,2016,6(7):34-37.
[28]姚宏波,廉洁,张善强,等.基于Wnt信号通路研究骨髓基质干细胞对阿尔茨海默病的治疗作用[J].世界最新医学信息文摘,2016,16(48):62.
[29]Wijesuriya HC,Bullock JY,Faull RL,et al.ABC efflux transporters in brain vasculature of Alzheimer’s subjects[J].Brain Res,2010,1358:228-238.
[30]Alvarez AR,Godoy JA,Mullendorff K,et al.Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons[J].Exp Cell Res,2004,297(1):186-196.
[31]Quintanilla RA,Munoz FJ,Metcalfe MJ,et al.Trolox and 17beta-estradiol protect against amyloid beta-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway[J].JBiol Chem,2005,280(12):11615-11625.
[32]Parr C,Mirzaei N,Christian M,et al.Activation of the Wnt/betacatenin pathway represses the transcription of the beta-amyloid precursor protein cleaving enzyme(BACE1)via binding of T-cell factor-4 to BACE1 promoter[J].FASEB J,2015,29(2):623-635.
[33]De Ferrari GV,Chacon MA,Barria MI,et al.Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils[J].Mol Psychiatry,2003,8(2):195-208.
[34]Huang M,Liang Y,Chen H,et al.The role of fluoxetine in activating Wnt/beta-catenin signaling and repressing beta-amyloid production in an Alzheimer mouse model[J].Front Aging Neurosci,2018,10:164.
[35]Jin N,Zhu H,Liang X,et al.Sodium selenate activated Wnt/beta-catenin signaling and repressed amyloid-beta formation in a triple transgenic mouse model of Alzheimer’s disease[J].Exp Neurol,2017,297:36-49.
[36]Park SY,Shin HK,Lee WS,et al.Neuroprotection by aripiprazole against beta-amyloid-induced toxicity by P-CK2alpha activation via inhibition of GSK-3beta[J].Oncotarget,2017,8(66):110380-110391.
[37]Vallee A,Lecarpentier Y,Guillevin R,et al.Effects of cannabidiol interactions with Wnt/beta-catenin pathway and PPARgamma on oxidative stress and neuroinflammation in Alzheimer’s disease[J].Acta Biochim Biophys Sin(Shanghai),2017,49(10):853-866.
[38]曾克武,王学美,富宏,等.淫羊藿苷通过Wnt/β-catenin信号通路抑制淀粉样蛋白Aβ_(25-35)所诱导的神经毒性[J].中国药学杂志,2011,46(22):1719-1722.
[39]吴明,朱元贵,潘晓东,等.雷公藤氯内酯醇通过激活Wnt/β-catenin通路减轻寡聚态Aβ_(1-42)诱导的神经元凋亡[J].药学学报,2010,58(7):853-859.
[40]Keane KM,Haskell-Ramsay CF,Veasey RC,et al.Montmorency Tart cherries(Prunus cerasus L.)modulate vascular function acutely,in the absence of improvement in cognitive performance[J].Br J Nutr,2016,116(11):1935-1944.
[41]Mandelkow EM,Mandelkow E.Biochemistry and cell biology of tau protein in neurofibrillary degeneration[J].Cold Spring Harb Perspect Med,2012,2(7):a006247.
[42]Hernandez F,Lucas JJ,Avila J.GSK3 and tau:two convergence points in Alzheimer’s disease[J].J Alzheimers Dis,2013,33(s1):141-144.
[43]Kremer A,Louis JV,Jaworski T,et al.GSK3 and Alzheimer’s disease:facts and fiction[J].Front Mol Neurosci,2011,4:17.
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