Research progress of Wnt/β-catenin signaling pathway in central nervous system diseases

doi:10.3877/cma.j.issn.2095-655X.2025.02.011

Abstract

Abstract:

The classical Wnt signaling pathway， namely Wnt/β-catenin signaling pathway， is involved in promoting embryo and tissue development， neural function integration and other physiological effects. With the establishment of the complex pathway structure network in the study， the positive and negative regulatory mechanisms of the Wnt/β-catenin pathway in various pathophysiological processes have been gradually discovered. The biological effects of distinct ligands vary significantly， including neuroprotective effects， oxidative stress and neuroinflammatory regulation， autophagy and apoptosis， etc. It is widely present in the occurrence and development of neurological diseases such as ischemic stroke，Alzheimer disease and Parkinson disease. Studies have shown that targeted regulation of the Wnt/β-catenin signaling pathway shows significant potential in restoring neurobiological function and treating central nervous system diseases. This review focuses on the research progress of Wnt/β-catenin signaling pathway involved in central nervous system diseases.

Key words: Wnt signaling pathway, Beta catenin, Brain infarction, Alzheimer disease, Parkinson disease

Size Wang, Chunmei Wang. Research progress of Wnt/β-catenin signaling pathway in central nervous system diseases[J]. Chinese Journal of Diagnostics(Electronic Edition), 2025, 13(02): 133-139.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhzdxdzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-655X.2025.02.011

https://zhzdxdzzz.cma-cmc.com.cn/EN/Y2025/V13/I02/133

Figures/Tables 1

References 70

［1］	Wang Y， Liang J， Fang Y， et al. Burden of common neurologic diseases in Asian countries，1990-2019：an analysis for the global burden of disease study 2019［J］.Neurology，2023，100（21）：e2141-e2154.DOI：10.1212/WNL.0000000000207218.
［2］	Scheltens P，De Strooper B，Kivipelto M，et al.Alzheimer′s disease［J］.Lancet，2021，397（10284）：1577-1590.DOI：10.1016/S0140-6736（20）32205-4.
［3］	Hayes MT.Parkinson′s disease and Parkinsonism［J］.Am J Med，2019，132（7）：802-807.DOI：10.1016/j.amjmed.2019.03.001.
［4］	DeLong JH，Ohashi SN，O′Connor KC，et al.Inflammatory responses after ischemic stroke［J］.Semin Immunopathol，2022，44（5）：625-648.DOI：10.1007/s00281-022-00943-7.
［5］	Ajoolabady A， Wang S， Kroemer G， et al. Targeting autophagy in ischemic stroke：from molecular mechanisms to clinical therapeutics［J］.Pharmacol Ther，2021（225）：107848.DOI：10.1016/j.pharmthera.2021.107848.
［6］	Eisenmann DM.Wnt signaling［J］.WormBook，2005：1-17.DOI：10.1895/wormbook.1.7.1.
［7］	Semenov MV，Habas R，Macdonald BT，et al.SnapShot：noncanonical Wnt signaling pathways［J］.Cell，2007，131（7）：1378.DOI：10.1016/j.cell.2007.12.011.
［8］	Ma Q，Yu J，Zhang X，et al.Wnt/β-catenin signaling pathway-a versatile player in apoptosis and autophagy［J］.Biochimie，2023（211）：57-67.DOI：10.1016/j.biochi.2023.03.001.
［9］	Vallée A.Neuroinflammation in schizophrenia：the key role of the WNT/β-catenin pathway［J］.Int J Mol Sci，2022，23（5）.DOI：10.3390/ijms23052810.
［10］	MacDonald BT，He X.Frizzled and LRP5/6 receptors for Wnt/βcatenin signaling［J］.Cold Spring Harb Perspect Biol，2012，4（12）：a007880..DOI：10.1101/cshperspect.a007880.
［11］	Zeng X，Tamai K，Doble B，et al.A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation［J］.Nature，2005，438（7069）：873-877.DOI：10.1038/nature04185.
［12］	Kafka A，Bašic'-Kinda S，Pec'ina-Ŝlaus N.The cellular story of dishevelleds［J］.Croat Med J，2014，55（5）：459-467.DOI：10.3325/cmj.2014.55.459.
［13］	Wang Z，Li Z，Ji H.Direct targeting of β-catenin in the Wnt signaling pathway：current progress and perspectives［J］.Med Res Rev，2021，41（4）：2109-2129.DOI：10.1002/med.21787.
［14］	Vallée A，Lecarpentier Y.Crosstalk between peroxisome proliferatoractivated receptor gamma and the canonical WNT/β-catenin pathway in chronic inflammation and oxidative stress during carcinogenesis［J］.Front Immunol，2018（9）：745.DOI：10.3389/fimmu.2018.00745.
［15］	Doumpas N，Lampart F，Robinson MD，et al.TCF/LEF dependent and independent transcriptional regulation of Wnt/β-catenin target genes［J］.EMBO J，2019，38（2）：e98873.DOI：10.15252/embj.201798873.
［16］	Joksimovic M，Awatramani R.Wnt/β-catenin signaling in midbrain dopaminergic neuron specification and neurogenesis［J］.J Mol Cell Biol，2014，6（1）：27-33.DOI：10.1093/jmcb/mjt043.
［17］	Lie DC，Colamarino SA，Song HJ，et al.Wnt signalling regulates adult hippocampal neurogenesis［J］.Nature，2005，437（7063）：1370-1375.DOI：10.1038/nature04108.
［18］	Joksimovic M， Patel M， Taketo MM， et al. Ectopic Wnt/betacatenin signaling induces neurogenesis in the spinal cord and hindbrain floor plate［J］.PLoS One，2012，7（1）：e30266.DOI：10.1371/journal.pone.0030266.
［19］	Nouri N，Patel MJ，Joksimovic M，et al.Excessive Wnt/beta-catenin signaling promotes midbrain floor plate neurogenesis，but results in vacillating dopamine progenitors［J］.Mol Cell Neurosci，2015（68）：131-142.DOI：10.1016/j.mcn.2015.07.002.
［20］	Harland R.Neural induction［J］.Curr Opin Genet Dev，2000，10（4）：357-362.DOI：10.1016/s0959-437x（00）00096-4.
［21］	Chizhikov VV，Millen KJ.Mechanisms of roof plate formation in the vertebrate CNS［J］.Nat Rev Neurosci，2004，5（10）：808-812.DOI：10.1038/nrn1520.
［22］	Li X，Peng Z，Long L，et al.Wnt4-modified NSC transplantation promotes functional recovery after spinal cord injury［J］.FASEB J，2020，34（1）：82-94.DOI：10.1096/fj.201901478RR.
［23］	Collu GM，Hidalgo-Sastre A，Brennan K.Wnt-Notch signalling crosstalk in development and disease［J］.Cell Mol Life Sci，2014，71（18）：3553-3567.DOI：10.1007/s00018-014-1644-x.
［24］	Muβmann C，Hübner R，Trilck M，et al.HES5 is a key mediator of Wnt-3a-induced neuronal differentiation［J］.Stem Cells Dev，2014，23（12）：1328-1339.DOI：10.1089/scd.2013.0557.
［25］	Kuwabara T，Hsieh J，Muotri A，et al.Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis［J］.Nat Neurosci，2009，12（9）：1097-1105.DOI：10.1038/nn.2360.
［26］	Endo Y，Beauchamp E，Woods D，et al.Wnt-3a and Dickkopf-1 stimulate neurite outgrowth in Ewing tumor cells via a Frizzled3-and c-Jun N-terminal kinase-dependent mechanism［J］.Mol Cell Biol，2008，28（7）：2368-2379.DOI：10.1128/MCB.01780-07.
［27］	Ciani L，Marzo A，Boyle K，et al.Wnt signalling tunes neurotransmitter release by directly targeting synaptotagmin-1［J］.Nat Commun，2015（6）：8302.DOI：10.1038/ncomms9302.
［28］	Ramos-Fernández E，Tapia-Rojas C，Ramírez VT，et al.Wnt-7a stimulates dendritic spine morphogenesis and PSD-95 expression through canonical signaling［J］.Mol Neurobiol，2019，56（3）：1870-1882.DOI：10.1007/s12035-018-1162-1.
［29］	Narvaes RF，Furini C.Role of Wnt signaling in synaptic plasticity and memory［J］.Neurobiol Learn Mem，2022（187）：107558.DOI：10.1016/j.nlm.2021.107558.
［30］	Álvarez-Ferradas C，Wellmann M，Morales K，et al.Wnt-5a induces the conversion of silent to functional synapses in the hippocampus［J］.Front Mol Neurosci，2022（15）：1024034.DOI：10.3389/fnmol.2022.1024034.
［31］	Cerpa W，Godoy JA，Alfaro I，et al.Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons［J］.J Biol Chem，2008，283（9）：5918-5927.DOI：10.1074/jbc.M705943200.
［32］	Ru W，Liu X，Bae C，et al.Microglia mediate HIV-1 gp120-induced synaptic degeneration in spinal pain neural Circuits［J］.J Neurosci，2019，39（42）：8408-8421.DOI：10.1523/JNEUROSCI.2851-18.2019.
［33］	Obermeier B，Daneman R，Ransohoff RM.Development，maintenance and disruption of the blood-brain barrier［J］.Nat Med，2013，19（12）：1584-1596.DOI：10.1038/nm.3407.
［34］	Fetsko AR，Sebo DJ，Taylor MR.Brain endothelial cells acquire blood-brain barrier properties in the absence of Vegf-dependent CNS angiogenesis［J］.Dev Biol，2023（494）：46-59.DOI：10.1016/j.ydbio.2022.11.007.
［35］	Kakogiannos N，Scalise AA，Martini E，et al.GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system［J］.J Clin Invest，2024，134（15）：e165368.DOI：10.1172/JCI165368.
［36］	Xie C，Wang Y，Wang J，et al.Perlecan improves blood spinal cord barrier repair through the integrin β1/ROCK/MLC pathway after spinal cord injury［J］.Mol Neurobiol，2023，60（1）：51-67.DOI：10.1007/s12035-022-03041-9.
［37］	Luo Y，Zhang Y，Feng Y，et al.Prenatal exposure to low doses of benzophenone-3 elicits disruption of cortical vasculature in fetuses through perturbations in Wnt/β-catenin signaling correlating with depression-like behavior in offspring mice［J］.Toxicology，2024（509）：153960.DOI：10.1016/j.tox.2024.153960.
［38］	Boyé K，Geraldo LH，Furtado J，et al.Endothelial Unc5B controls blood-brain barrier integrity［J］.Nat Commun，2022，13（1）：1169.DOI：10.1038/s41467-022-28785-9.
［39］	Manukjan N， Chau S， Caiment F， et al. Wnt7a decreases brain endothelial barrier function via β-catenin activation［J］.Mol Neurobiol，2024，61（7）：4854-4867.DOI：10.1007/s12035-023-03872-0.
［40］	GBD 2019 Stroke Collaborators. Global， regional， and national burden of stroke and its risk factors，1990-2019：a systematic analysis for the Global Burden of Disease Study 2019［J］.Lancet Neurol，2021，20（10）：795-820.DOI：10.1016/S1474-4422（21）00252-0.
［41］	Schölzke MN，Schwaninger M.Transcriptional regulation of neurogenesis：potential mechanisms in cerebral ischemia［J］.J Mol Med（Berl），2007，85（6）：577-588.DOI：10.1007/s00109-007-0196-z.
［42］	Li S，Li Y，Huang P，et al.Knockout of Rnf213 ameliorates cerebral ischemic-reperfusion injury by inhibiting neuronal apoptosis through the Akt/GSK-3β/β-catenin/Bcl-2 pathway［J］.Neuroscience，2023（533）：10-21.DOI：10.1016/j.neuroscience.2023.09.018.
［43］	Chen G，Rajkowska G，Du F，et al.Enhancement of hippocampal neurogenesis by lithium［J］.J Neurochem，2000，75（4）：1729-1734.DOI：10.1046/j.1471-4159.2000.0751729.x.
［44］	Kriska J，Janeckova L，Kirdajova D，et al.Wnt/β-catenin signaling promotes differentiation of ischemia-activated adult neural stem/progenitor cells to neuronal precursors［J］.Front Neurosci，2021（15）：628983.DOI：10.3389/fnins.2021.628983.
［45］	He W，Tian X，Lv M，et al.Liraglutide protects neurite outgrowth of cortical neurons under oxidative stress though activating the Wnt pathway［J］.J Stroke Cerebrovasc Dis，2018，27（10）：2696-2702.DOI：10.1016/j.jstrokecerebrovasdis.2018.05.039.
［46］	Feng X， Li M， Lin Z， et al. Tetramethylpyrazine promotes axonal remodeling and modulates microglial polarization via JAK2-STAT1/3 and GSK3-NFκB pathways in ischemic stroke［J］.Neurochem Int，2023 （170）：105607.DOI：10.1016/j.neuint.2023.105607.
［47］	Nadareishvili Z，Simpkins AN，Hitomi E，et al.Post-stroke bloodbrain barrier disruption and poor functional outcome in patients receiving thrombolytic therapy［J］.Cerebrovasc Dis，2019，47（3-4）：135-142.DOI：10.1159/000499666.
［48］	McMahon AP，Ichida JK.Repairing the blood-brain barrier［J］.Science，2022，375（6582）：715-716.DOI：10.1126/science.abn7921.
［49］	Ma B，Hottiger MO.Crosstalk between Wnt/β-catenin and NF-κB signaling pathway during inflammation［J］.Front Immunol，2016（7）：378.DOI：10.3389/fimmu.2016.00378.
［50］	Halleskog C，Dijksterhuis JP，Kilander MB，et al.Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation［J］.J Neuroinflammation，2012（9）：111.DOI：10.1186/1742-2094-9-111.
［51］	Mobaderi T，Kazemnejad A，Salehi M.Exploring the impacts of risk factors on mortality patterns of global Alzheimer's disease and related dementias from 1990 to 2021［J］.Sci Rep，2024，14（1）：15583.DOI：10.1038/s41598-024-65887-4.
［52］	Soria Lopez JA，González HM，Léger GC.Alzheimer′s disease［J］.Handb Clin Neurol，2019（167）：231-255.DOI：10.1016/B978-0-12-804766-8.00013-3.
［53］	Song L，Oseid DE，Wells EA，et al.The interplay between GSK3β and Tau Ser262 phosphorylation during the progression of Tau pathology［J］.Int J Mol Sci，2022，23（19）：11610.DOI：10.3390/ijms231911610.
［54］	Ivashko-Pachima Y，Gozes I.NAP Protects against Tau hyperphosphorylation through GSK3［J］.Curr Pharm Des，2018，24（33）：3868-3877.DOI：10.2174/1381612824666181112105954.
［55］	Medunjanin S，Schleithoff L，Fiegehenn C，et al.GSK-3β controls NF-kappa B activity via IKKγ/NEMO［J］.Sci Rep，2016（6）：38553.DOI：10.1038/srep38553.
［56］	Hu M，Zheng M，Wang C，et al.Andrographolide derivative Andro-Ⅲ modulates neuroinflammation and attenuates neuropathological changes of Alzheimer′s disease via GSK-3β/NF-κB/CREB pathway［J］.Eur J Pharmacol，2024（965）：176305.DOI：10.1016/j.ejphar.2023.176305.
［57］	Yang Y，Wang L，Zhang C，et al.Ginsenoside Rg1 improves Alzheimer′s disease by regulating oxidative stress，apoptosis，and neuroinflammation through Wnt/GSK-3β/β-catenin signaling pathway［J］.Chem Biol Drug Des，2022，99（6）：884-896.DOI：10.1111/cbdd.14041.
［58］	Dubey T， Kushwaha P， Thulasiram HV， et al. Bacopa monnieri reduces Tau aggregation and Tau-mediated toxicity in cells［J］.Int J Biol Macromol，2023（234）：123171.DOI：10.1016/j.ijbiomac.2023.123171.
［59］	Li HL，Wang HH，Liu SJ，et al.Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin，a mechanism involved in Alzheimer′s neurodegeneration［J］.Proc Natl Acad Sci U S A，2007，104（9）：3591-3596.DOI：10.1073/pnas.0609303104.
［60］	Xu T，Dong W，Liu J，et al.Disease burden of Parkinson′s disease in China and its provinces from 1990 to 2021：findings from the global burden of disease study 2021［J］.Lancet Reg Health West Pac，2024（46）：101078.DOI：10.1016/j.lanwpc.2024.101078.
［61］	Mahul-Mellier AL，Burtscher J，Maharjan N，et al.The process of Lewy body formation，rather than simply α-synuclein fibrillization，is one of the major drivers of neurodegeneration［J］.Proc Natl Acad Sci U S A，2020，117（9）：4971-4982.DOI：10.1073/pnas.1913904117.
［62］	Wakabayashi K，Tanji K，Odagiri S，et al.The Lewy body in Parkinson′s disease and related neurodegenerative disorders［J］.Mol Neurobiol，2013，47（2）：495-508.DOI：10.1007/s12035-012-8280-y.
［63］	程丽萍，王浩，车峰远，等.α-突触核蛋白通过抑制Wnt/β-catenin信号通路参与帕金森病发病机制［J］.中风与神经疾病杂志，2019，36（1）：10-14.
［64］	Huang YL，Zhang JN，Hou TZ，et al.Inhibition of Wnt/β-catenin signaling attenuates axonal degeneration in models of Parkinson′s disease［J］.Neurochem Int，2022（159）：105389.DOI：10.1016/j.neuint.2022.105389.
［65］	Geng X，Zou Y，Li J，et al.Mesenchymal stem cell exosomes rich in miR-23b-3p affect the Wnt signaling pathway and promote neuronal autophagy to alleviate PD symptoms［J］.Neurosci Lett，2023（814）：137437.DOI：10.1016/j.neulet.2023.137437.
［66］	Surmeier DJ.Determinants of dopaminergic neuron loss in Parkinson′s disease［J］.FEBS J，2018，285（19）：3657-3668.DOI：10.1111/febs.14607.
［67］	Samim Khan S，Janrao S，Srivastava S，et al.GSK-3β：an exuberating neuroinflammatory mediator in Parkinson′s disease［J］.Biochem Pharmacol，2023（210）：115496.DOI：10.1016/j.bcp.2023.115496.
［68］	Huang B，Liu J，Meng T，et al.Polydatin prevents lipopolysaccharide（LPS）-induced Parkinson's disease via regulation of the AKT/GSK3β-Nrf2/NF-κB signaling axis［J］.Front Immunol，2018（9）：2527.DOI：10.3389/fimmu.2018.02527.
［69］	L'Episcopo F，Tirolo C，Peruzzotti-Jametti L，et al.Neural stem cell grafts promote astroglia-driven neurorestoration in the aged Parkinsonian brain via Wnt/β-catenin signaling［J］.Stem Cells，2018，36（8）：1179-1197.DOI：10.1002/stem.2827.
［70］	Rawal N，Corti O，Sacchetti P，et al.Parkin protects dopaminergic neurons from excessive Wnt/beta-catenin signaling［J］.Biochem Biophys Res Commun，2009，388（3）：473-478.DOI：10.1016/j.bbrc.2009.07.014.

[1]	Jialin Han, Pinjing Hui, Yanhong Yan, Chunhong Hu, Qi Fang. Correlation between cerebral hemodynamic parameters and cerebral infarction volume in patients with chronic middle cerebral artery occlusion [J]. Chinese Journal of Medical Ultrasound (Electronic Edition), 2019, 16(08): 602-608.
[2]	Wenkai Wan, Yihong Xu, Weidong Xu. Progress in ossification of ankylosing spondylitis [J]. Chinese Journal of Joint Surgery(Electronic Edition), 2019, 13(03): 348-352.
[3]	Wei Zhou, Heng Cai, Haidi Fan, Huizhong Li, Chuanxia Wang, Maosheng Gu. Mechanism of MMACHC gene mutation of cblC-type methylmalonic acidemia on apoptosis and Wnt/β-catenin signaling pathway in mouse neural cells [J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2022, 18(05): 528-539.
[4]	Weifei Wang, Haiyan Yu, Xiaoling Yuan, Min Zhao, Min Wang, Qian Lu, Tian Wang, Dianrong Gong. Clinical effects of umbilical cord blood mononuclear cell transplantation on Parkinson's disease [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2020, 10(06): 341-345.
[5]	Yu Song, Xiuli Bao. Research progress of Dickkopf-1 in ocular fibrosis [J]. Chinese Journal of Ophthalmologic Medicine(Electronic Edition), 2022, 12(06): 362-366.
[6]	Yuanyuan Dang, Xiaoyu Xia, Yi Yang, Nan Liu, Tonghui Shan, Shaopeng Du, Zhiqiang Zhang, Jianghong He. Effect of asleep STN-DBS guided by image alone under general anesthesia in patients with Parkinson’s disease [J]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2020, 06(06): 350-355.
[7]	Qianru Zhou, Jiali Ren, Yuanwei Wang, Ting Hu, Guangsheng Wang. Diagnostic value of morphological features detected by diffusion weighted imaging in anterior choroidal artery infarction [J]. Chinese Journal of Clinicians(Electronic Edition), 2019, 13(09): 669-674.
[8]	Jing Ding, Peiwen Li, Yingchun Xu. The application of Xingnao Kaiqiao acupuncture in severe neurological emergencies [J]. Chinese Journal of Acupuncture and Moxibustion(Electronic Edition), 2023, 12(04): 161-164.
[9]	Lina Ning, Jie Xiong. The therapeutic evaluation research on treating dysarthria after cerebral infarction with Xingnao Kaiqiao acupuncture and tongue acupuncture therapy [J]. Chinese Journal of Acupuncture and Moxibustion(Electronic Edition), 2023, 12(04): 146-150.
[10]	Min Huang, Bohong Kan. Clinical research progress on acupuncture treatment of Parkinson's disease [J]. Chinese Journal of Acupuncture and Moxibustion(Electronic Edition), 2021, 10(02): 59-62.
[11]	Yunchen Xu, Liaoyao Wang, Jian Pei. Correlation between apolipoprotein E gene polymorphism and Alzheimer′s disease syndrome type in traditional Chinese medicine [J]. Chinese Journal of Acupuncture and Moxibustion(Electronic Edition), 2020, 09(04): 142-145.
[12]	Lin Liu, Wenhuan Zhang, Yaru Song, Yunlu Jiang. Research advances of the neuroprotective mechanism of apelin-13 in Alzheimer disease [J]. Chinese Journal of Diagnostics(Electronic Edition), 2024, 12(04): 276-280.
[13]	Ruye Guo, Liming Meng, Nan Chen, Yuying Song, Haiyan Yin, Yan Guo. Research status on the neuroprotective efficacy and mechanism of Apelin/APJ system in Parkinson disease model [J]. Chinese Journal of Diagnostics(Electronic Edition), 2023, 11(04): 276-282.
[14]	Qian Liu, Xin Li, Xin Liu, Jinxiang Yuan. Research progress of ferroptosis in the pathogenesis of Alzheimer′s disease [J]. Chinese Journal of Diagnostics(Electronic Edition), 2022, 10(03): 211-215.
[15]	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.

Please choose a citation manager

Content to export