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Abstract

A serine/threonine kinase with a wide variety of substrates, Glycogen Synthase Kinase-3 (GSK-3) is widely expressed. GSK-3 is a key player in cell metabolism and signaling, modulating numerous cellular functions and playing significant roles in both healthy and diseased states. The two histopathological features of Alzheimer's disease, the intracellular neurofibrillary tangles composed of hyperphosphorylated tau, and the extracellular senile plaques composed of beta-amyloid, have been linked to GSK-3. It alters multiple tau protein locations found in neurofibrillary tangles. Additionally, GSK-3 can react to this peptide and regulate the production of beta-amyloid. The overexpression of GSK-3 in several transgenic models has been linked to tau hyperphosphorylation, neuronal death, and a reduction in cognitive function. It has been shown that lithium, a medication commonly used to treat affective disorders, inhibits at therapeutically relevant concentrations and stops tau phosphorylation. In this review, we provide an overview of the most recent research on the potential of GSK-3 inhibitors for treating Alzheimer's disease.

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References

  1. Mendez M.F. Early-onset Alzheimer disease and its variants. Continuum (Minneap. Minn.) 2019 25 1 34 51 10.1212/CON.0000000000000687 30707186
    [Google Scholar]
  2. Rujeedawa T. Carrillo Félez E. Clare I.C.H. The clinical and neuropathological features of sporadic (Late-onset) and genetic forms of alzheimer’s disease. J. Clin. Med. 2021 10 19 4582 10.3390/jcm10194582 34640600
    [Google Scholar]
  3. Attiah I. Redha L. Ansari S.A. Cognitive impairments by formaldehyde exposure in Alzheimer’s disease. Aging Health Res 2024 4 2 100194 10.1016/j.ahr.2024.100194
    [Google Scholar]
  4. Snyder H.M. Asthana S. Bain L. Sex biology contributions to vulnerability to Alzheimer’s disease: A think tank convened by the Women’s Alzheimer’s Research Initiative. Alzheimers Dement. 2016 12 11 1186 1196 10.1016/j.jalz.2016.08.004 27692800
    [Google Scholar]
  5. Laws K.R. Irvine K. Gale T.M. Sex differences in cognitive impairment in Alzheimer’s disease. World J. Psychiatry 2016 6 1 54 65 10.5498/wjp.v6.i1.54 27014598
    [Google Scholar]
  6. Sohn D. Shpanskaya K. Lucas J.E. Sex differences in cognitive decline in subjects with high likelihood of mild cognitive impairment due to alzheimer’s disease. Sci. Rep. 2018 8 1 7490 10.1038/s41598‑018‑25377‑w 29748598
    [Google Scholar]
  7. Burke S.L. Hu T. Fava N.M. Sex differences in the development of mild cognitive impairment and probable Alzheimer’s disease as predicted by hippocampal volume or white matter hyperintensities. J. Women Aging 2019 31 2 140 164 10.1080/08952841.2018.1419476 29319430
    [Google Scholar]
  8. Brann D.W. Dhandapani K. Wakade C. Mahesh V.B. Khan M.M. Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications. Steroids 2007 72 5 381 405 10.1016/j.steroids.2007.02.003 17379265
    [Google Scholar]
  9. Klein S.L. Flanagan K.L. Sex differences in immune responses. Nat. Rev. Immunol. 2016 16 10 626 638 10.1038/nri.2016.90 27546235
    [Google Scholar]
  10. Onisiforou A. Christodoulou C.C. Zamba-Papanicolaou E. Zanos P. Georgiou P. Transcriptomic analysis reveals sex-specific patterns in the hippocampus in Alzheimer’s disease. Front. Endocrinol. 2024 15 1345498 10.3389/fendo.2024.1345498 38689734
    [Google Scholar]
  11. Piaceri I. Nacmias B. Sorbi S. Genetics of familial and sporadic Alzheimer s disease. Front. Biosci. 2013 E5 1 167 177 10.2741/E605 23276979
    [Google Scholar]
  12. Vasefi M. Ghaboolian-Zare E. Abedelwahab H. Osu A. Environmental toxins and Alzheimer’s disease progression. Neurochem. Int. 2020 141 104852 10.1016/j.neuint.2020.104852 33010393
    [Google Scholar]
  13. Alsayyah A. ElMazoudy R. Al-Namshan M. Al-Jafary M. Alaqeel N. Chronic neurodegeneration by aflatoxin B1 depends on alterations of brain enzyme activity and immunoexpression of astrocyte in male rats. Ecotoxicol. Environ. Saf. 2019 182 109407 10.1016/j.ecoenv.2019.109407 31279280
    [Google Scholar]
  14. Dhapola R. Sharma P. Kumari S. Bhatti J.S. Hari K.R.D. Environmental toxins and alzheimer’s disease: A comprehensive analysis of patho-genic mechanisms and therapeutic modulation. Mol. Neurobiol. 2024 61 6 3657 3677 10.1007/s12035‑023‑03805‑x 38006469
    [Google Scholar]
  15. Guo B. Ba Q. [Environmental pollutants and Alzheimer’s disease] Sheng Li Xue Bao 2023 75 6 740 766 38151341
    [Google Scholar]
  16. Onisiforou A. Zanos P. From viral infections to Alzheimer’s disease: Unveiling the mechanistic links through systems bioinformatics. J. Infect. Dis. 2024 230 Supplement. 2 S128 S140 10.1093/infdis/jiae242 39255398 PMC11385591
    [Google Scholar]
  17. Tang B.C. Wang Y.T. Ren J. Basic information about memantine and its treatment of Alzheimer’s disease and other clinical applications. Ibrain 2023 9 3 340 348 10.1002/ibra.12098 37786758
    [Google Scholar]
  18. Zhang Y. Chen H. Li R. Sterling K. Song W. Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future. Signal Transduct. Target. Ther. 2023 8 1 248 10.1038/s41392‑023‑01484‑7 37386015
    [Google Scholar]
  19. Marucci G. Buccioni M. Ben D.D. Lambertucci C. Volpini R. Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 2021 190 108352 10.1016/j.neuropharm.2020.108352 33035532
    [Google Scholar]
  20. Marotta G. Basagni F. Rosini M. Minarini A. Memantine derivatives as multitarget agents in alzheimer’s disease. Molecules 2020 25 17 4005 10.3390/molecules25174005 32887400
    [Google Scholar]
  21. Beurel E. Grieco S.F. Jope R.S. Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases. Pharmacol. Ther. 2015 148 114 131 10.1016/j.pharmthera.2014.11.016 25435019
    [Google Scholar]
  22. Popkie A.P. Zeidner L.C. Albrecht A.M. Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regu-lates DNA methylation of imprinted loci. J. Biol. Chem. 2010 285 53 41337 41347 10.1074/jbc.M110.170704 21047779
    [Google Scholar]
  23. Ciaraldi T.P. Carter L. Mudaliar S. Henry R.R. GSK-3β and control of glucose metabolism and insulin action in human skeletal muscle. Mol. Cell. Endocrinol. 2010 315 1-2 153 158 10.1016/j.mce.2009.05.020 19505532
    [Google Scholar]
  24. Embi N. Rylatt D.B. Cohen P. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J. Biochem. 1980 107 2 519 527 10.1111/j.1432‑1033.1980.tb06059.x 6249596
    [Google Scholar]
  25. Medunjanin S. Schleithoff L. Fiegehenn C. Weinert S. Zuschratter W. Braun-Dullaeus R.C. GSK-3β controls NF-kappaB activity via IKKγ/NEMO. Sci. Rep. 2016 6 1 38553 10.1038/srep38553 27929056
    [Google Scholar]
  26. Hermida M.A. Dinesh K.J. Leslie N.R. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv. Biol. Regul. 2017 65 5 15 10.1016/j.jbior.2017.06.003 28712664
    [Google Scholar]
  27. Wang L. Li J. Di L. Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases. Med. Res. Rev. 2022 42 2 946 982 10.1002/med.21867 34729791
    [Google Scholar]
  28. Hoffmeister L. Diekmann M. Brand K. Huber R. GSK3: A kinase balancing promotion and resolution of inflammation. Cells 2020 9 4 820 10.3390/cells9040820 32231133
    [Google Scholar]
  29. Jope R.S. Cheng Y. Lowell J.A. Worthen R.J. Sitbon Y.H. Beurel E. Stressed and inflamed, can GSK3 be blamed? Trends Biochem. Sci. 2017 42 3 180 192 10.1016/j.tibs.2016.10.009 27876551
    [Google Scholar]
  30. Guo N. Wang X. Xu M. Bai J. Yu H. Le Zhang. PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depres-sion. Pharmacol. Res. 2024 206 107300 10.1016/j.phrs.2024.107300 38992850
    [Google Scholar]
  31. Barr J.L. Unterwald E.M. Glycogen synthase kinase-3 signaling in cellular and behavioral responses to psychostimulant drugs. Biochim. Biophys. Acta Mol. Cell Res. 2020 1867 9 118746 10.1016/j.bbamcr.2020.118746 32454064
    [Google Scholar]
  32. Mancinelli R. Carpino G. Petrungaro S. Multifaceted roles of GSK‐3 in cancer and autophagy‐related diseases. Oxid. Med. Cell. Longev. 2017 2017 1 4629495 10.1155/2017/4629495 29379583
    [Google Scholar]
  33. Zhong J. Yu X. Zhong Y. GSK-3β inhibitor amplifies autophagy-lysosomal pathways by regulating TFEB in Parkinson’s disease models. Exp. Neurol. 2025 383 115033 10.1016/j.expneurol.2024.115033 39490621
    [Google Scholar]
  34. Sotolongo K. Ghiso J. Rostagno A. Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage. Alzheimers Res. Ther. 2020 12 1 13 10.1186/s13195‑019‑0578‑9 31931869
    [Google Scholar]
  35. Walz A. Ugolkov A. Chandra S. Molecular pathways: Revisiting glycogen synthase kinase-3β as a target for the treatment of cancer. Clin. Cancer Res. 2017 23 8 1891 1897 10.1158/1078‑0432.CCR‑15‑2240 28053024
    [Google Scholar]
  36. Besing R.C. Paul J.R. Hablitz L.M. Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus. J. Biol. Rhythms 2015 30 2 155 160 10.1177/0748730415573167 25724980
    [Google Scholar]
  37. Kimura T. Yamashita S. Nakao S. GSK-3β is required for memory reconsolidation in adult brain. PLoS One 2008 3 10 e3540 10.1371/journal.pone.0003540 18958152
    [Google Scholar]
  38. Chuang D.M. Wang Z. Chiu C.T. GSK-3 as a target for lithium-induced neuroprotection against excitotoxicity in neuronal cultures and ani-mal models of ischemic stroke. Front. Mol. Neurosci. 2011 4 15 10.3389/fnmol.2011.00015 21886605
    [Google Scholar]
  39. Takashima A. GSK-3 is essential in the pathogenesis of Alzheimer’s disease. J. Alzheimers Dis. 2006 9 s3 309 317 [Suppl. 10.3233/JAD‑2006‑9S335 16914869
    [Google Scholar]
  40. Masters C.L. Multhaup G. Simms G. Pottgiesser J. Martins R.N. Beyreuther K. Neuronal origin of a cerebral amyloid: Neurofibrillary tan-gles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 1985 4 11 2757 2763 10.1002/j.1460‑2075.1985.tb04000.x 4065091
    [Google Scholar]
  41. Avila J. Hernández F. GSK-3 inhibitors for Alzheimer’s disease. Expert Rev. Neurother. 2007 7 11 1527 1533 10.1586/14737175.7.11.1527 17997701
    [Google Scholar]
  42. Sayas C.L. Ávila J. GSK-3 and Tau: A key duet in Alzheimer’s disease. Cells 2021 10 4 721 10.3390/cells10040721 33804962 PMC8063930
    [Google Scholar]
  43. Lei P. Ayton S. Bush A.I. Adlard P.A. GSK‐3 in neurodegenerative diseases. Int. J. Alzheimers Dis. 2011 2011 1 189246 10.4061/2011/189246 21629738
    [Google Scholar]
  44. Eldar-Finkelman H. Licht-Murava A. Pietrokovski S. Eisenstein M. Substrate competitive GSK-3 inhibitors - strategy and implications. Biochim. Biophys. Acta. Proteins Proteomics 2010 1804 3 598 603 10.1016/j.bbapap.2009.09.010 19770076
    [Google Scholar]
  45. Jope R.S. Lithium and GSK-3: One inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol. Sci. 2003 24 9 441 443 10.1016/S0165‑6147(03)00206‑2 12967765
    [Google Scholar]
  46. Bradley C.A. Peineau S. Taghibiglou C. A pivotal role of GSK-3 in synaptic plasticity. Front. Mol. Neurosci. 2012 5 13 10.3389/fnmol.2012.00013 22363262
    [Google Scholar]
  47. Snitow M.E. Bhansali R.S. Klein P.S. Lithium and therapeutic targeting of GSK-3. Cells 2021 10 2 255 10.3390/cells10020255 33525562
    [Google Scholar]
  48. Gitlin M. Lithium side effects and toxicity: Prevalence and management strategies. Int. J. Bipolar Disord. 2016 4 1 27 10.1186/s40345‑016‑0068‑y 27900734
    [Google Scholar]
  49. Zhang J. Zhang Y. Wang J. Xia Y. Zhang J. Chen L. Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies. Signal Transduct. Target. Ther. 2024 9 1 211 10.1038/s41392‑024‑01911‑3 39174535
    [Google Scholar]
  50. Mathuram T. Reece L. Cherian K. GSK-3 inhibitors: A double-edged sword?-An update on tideglusib. Drug Res. 2018 68 8 436 443 10.1055/s‑0044‑100186 29388174
    [Google Scholar]
  51. Domínguez J.M. Fuertes A. Orozco L. del Monte-Millán M. Delgado E. Medina M. Evidence for irreversible inhibition of glycogen syn-thase kinase-3β by tideglusib. J. Biol. Chem. 2012 287 2 893 904 10.1074/jbc.M111.306472 22102280
    [Google Scholar]
  52. Perez D.I. Palomo V. Pérez C. Switching reversibility to irreversibility in glycogen synthase kinase 3 inhibitors: Clues for specific design of new compounds. J. Med. Chem. 2011 54 12 4042 4056 10.1021/jm1016279 21500862
    [Google Scholar]
  53. Diniz B. Machado-Vieira R. Forlenza O.V. Lithium and neuroprotection: Translational evidence and implications for the treatment of neu-ropsychiatric disorders. Neuropsychiatr. Dis. Treat. 2013 9 493 500 10.2147/NDT.S33086 23596350
    [Google Scholar]
  54. Pérez M. Hernández F. Lim F. Díaz-Nido J. Avila J. Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J. Alzheimers Dis. 2003 5 4 301 308 10.3233/JAD‑2003‑5405 14624025
    [Google Scholar]
  55. Noble W. Planel E. Zehr C. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc. Natl. Acad. Sci. USA 2005 102 19 6990 6995 10.1073/pnas.0500466102 15867159
    [Google Scholar]
  56. Nakashima H. Ishihara T. Suguimoto P. Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol. 2005 110 6 547 556 10.1007/s00401‑005‑1087‑4 16228182
    [Google Scholar]
  57. Caccamo A. Oddo S. Tran L.X. LaFerla F.M. Lithium reduces tau phosphorylation but not A β or working memory deficits in a transgenic model with both plaques and tangles. Am. J. Pathol. 2007 170 5 1669 1675 10.2353/ajpath.2007.061178 17456772
    [Google Scholar]
  58. Rodríguez-Matellán A. Avila J. Hernández F. Overexpression of GSK-3β in adult Tet-OFF GSK-3β transgenic mice, and not during em-bryonic or postnatal development, induces tau phosphorylation, neurodegeneration and learning deficits. Front. Mol. Neurosci. 2020 13 561470 10.3389/fnmol.2020.561470 33013321
    [Google Scholar]
  59. Ferensztajn-Rochowiak E. Rybakowski J.K. Long-term lithium therapy: Side effects and interactions. Pharmaceuticals 2023 16 1 74 10.3390/ph16010074 36678571
    [Google Scholar]
  60. del Ser T. Steinwachs K.C. Gertz H.J. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: A pilot study. J. Alzheimers Dis. 2012 33 1 205 215 10.3233/JAD‑2012‑120805 22936007
    [Google Scholar]
  61. Lovestone S. Boada M. Dubois B. A phase II trial of tideglusib in Alzheimer’s disease. J. Alzheimers Dis. 2015 45 1 75 88 10.3233/JAD‑141959 25537011
    [Google Scholar]
  62. Gentles R.G. Hu S. Dubowchik G.M. Recent advances in the discovery of GSK-3 inhibitors and a perspective on their utility for the treat-ment of Alzheimer’s disease. Annu. Rep. Med. Chem. 2009 44 3 26 10.1016/S0065‑7743(09)04401‑7
    [Google Scholar]
  63. Pan H.Y. Valapala M. Regulation of autophagy by the glycogen synthase kinase-3 (gsk-3) signaling pathway. Int. J. Mol. Sci. 2022 23 3 1709 10.3390/ijms23031709 35163631
    [Google Scholar]
  64. Shri S.R. Manandhar S. Nayak Y. Pai K.S.R. Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease. Adv. Pharm. Bull. 2023 13 4 688 700 10.34172/apb.2023.071 38022801
    [Google Scholar]
  65. Griebel G. Stemmelin J. Lopez-Grancha M. The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenu-ates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer’s disease in rodents. Sci. Rep. 2019 9 1 18045 10.1038/s41598‑019‑54557‑5 31792284
    [Google Scholar]
  66. Arciniegas Ruiz S.M. Eldar-Finkelman H. Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade On-ward. Front. Mol. Neurosci. 2022 14 792364 10.3389/fnmol.2021.792364 35126052
    [Google Scholar]
  67. Yang J. Nie J. Ma X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol. Cancer 2019 18 26 10.1186/s12943‑019‑0954‑x 30717740
    [Google Scholar]
  68. Kitagishi Y. Kobayashi M. Kikuta K. Matsuda S. Roles of PI3K/AKT/GSK3/mTOR pathway in cell signaling of mental illnesses. Depress. Res. Treat. 2012 2012 1 8 10.1155/2012/752563 23320155
    [Google Scholar]
  69. Liu R. Chen Y. Liu G. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020 11 9 797 10.1038/s41419‑020‑02998‑6 32973135
    [Google Scholar]
  70. Toader C. Tataru C.P. Munteanu O. Serban M. Covache-Busuioc R-A. Ciurea A.V. Serban M. Covache-Busuioc R A. Ciurea AV Enyedi M. Decoding neurodegeneration: A review of molecular mechanisms and therapeutic advances in Alzheimer’s, Parkinson’s, and ALS. Int. J. Mol. Sci. 2024 25 12613 10.3390/ijms252312613
    [Google Scholar]
  71. Glaviano A. Foo A.S.C. Lam H.Y. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol. Cancer 2023 22 1 138 10.1186/s12943‑023‑01827‑6 37596643
    [Google Scholar]
  72. Zhong W. Darmani N.A. Role of PI3K/Akt/GSK-3 Pathway in emesis and potential new antiemetics. J Cell Signal 2020 1 4 155 159 10.33696/Signaling.1.024 33426544
    [Google Scholar]
  73. Ansari S.A. Alshanberi A.M. Satar R. Abujamai J. Ashraf G.M. Current updates on nanotechnology-based drug delivery platforms for treat-ing alzheimer’s with herbal drugs. Pharm. Nanotechnol. 2024 13 10.2174/0122117385335626241204165702 39716798
    [Google Scholar]
  74. Rippin I. Khazanov N. Ben Joseph S. Discovery and design of novel small molecule gsk-3 inhibitors targeting the substrate binding site. Int. J. Mol. Sci. 2020 21 22 8709 10.3390/ijms21228709 33218072
    [Google Scholar]
  75. Hanks S.K. Hunter T. The eukaryotic protein kinase superfamily: Kinase (catalytic) domain structure and classification. FASEB J. 1995 9 8 576 596 10.1096/fasebj.9.8.7768349 7768349
    [Google Scholar]
  76. Taylor S.S. Kornev A.P. Protein kinases: Evolution of dynamic regulatory proteins. Trends Biochem. Sci. 2011 36 2 65 77 10.1016/j.tibs.2010.09.006 20971646
    [Google Scholar]
  77. Lo Monte F. Kramer T. Gu J. Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-3α. J. Med. Chem. 2012 55 9 4407 4424 10.1021/jm300309a 22533818
    [Google Scholar]
  78. Chen Z. Yang Y. Li M. Whole‐brain neural connectivity to cholinergic neurons in the nucleus basalis of Meynert. J. Neurochem. 2023 166 2 233 247 10.1111/jnc.15873 37353897
    [Google Scholar]
  79. Asl F.S.S. Malverdi N. Mojahedian F. Baziyar P. Nabi-Afjadi M. Discovery of effective GSK-3β inhibitors as therapeutic potential against Alzheimer’s disease: A computational drug design insight. Int. J. Biol. Macromol. 2025 306 Pt 1 141273 10.1016/j.ijbiomac.2025.141273 39978523
    [Google Scholar]
  80. Arfeen M. Patel R. Khan T. Bharatam P.V. Molecular dynamics simulation studies of GSK-3β ATP competitive inhibitors: Understanding the factors contributing to selectivity. J. Biomol. Struct. Dyn. 2015 33 12 2578 2593 10.1080/07391102.2015.1063457 26209183
    [Google Scholar]
  81. Leost M. Schultz C. Link A. Paullones are potent inhibitors of glycogen synthase kinase‐3β and cyclin‐dependent kinase 5/p25. Eur. J. Biochem. 2000 267 19 5983 5994 10.1046/j.1432‑1327.2000.01673.x 10998059
    [Google Scholar]
  82. Hanna S. Aly R. Eldeen G.N. Adanero V.A. Pérez A.R. Small Molecule GSK-3 Inhibitors Safely Promote the Proliferation and Viability of Human Dental Pulp Stem Cells—In Vitro. Biomedicines 2023 11 2 542 10.3390/biomedicines11020542 36831078
    [Google Scholar]
  83. Sivaprakasam P. Han X. Civiello R.L. Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth ex-ploration of chemical space around a pyrrolopyridinone core. Bioorg. Med. Chem. Lett. 2015 25 9 1856 1863 10.1016/j.bmcl.2015.03.046 25845281
    [Google Scholar]
  84. Patel P. Woodgett J.R. Glycogen synthase kinase 3: A kinase for all pathways? Curr. Top. Dev. Biol. 2017 123 277 302 10.1016/bs.ctdb.2016.11.011 28236969
    [Google Scholar]
  85. Sciú M.L. Sebastián-Pérez V. Martinez-Gonzalez L. Computer-aided molecular design of pyrazolotriazines targeting glycogen syn-thase kinase 3. J. Enzyme Inhib. Med. Chem. 2019 34 1 87 96 10.1080/14756366.2018.1530223 30362380
    [Google Scholar]
  86. Tolosa E. Litvan I. Höglinger G.U. A phase 2 trial of the GSK‐3 inhibitor tideglusib in progressive supranuclear palsy. Mov. Disord. 2014 29 4 470 478 10.1002/mds.25824 24532007
    [Google Scholar]
  87. Höglinger G.U. Huppertz H.J. Wagenpfeil S. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. Mov. Disord. 2014 29 4 479 487 10.1002/mds.25815 24488721
    [Google Scholar]
  88. Zhu J. Wu Y. Xu L. Jin J. Theoretical studies on the selectivity mechanisms of glycogen synthase kinase 3Î2 (GSK3Î2) with pyrazine ATP-competitive inhibitors by 3DQSAR, molecular docking, molecular dynamics simulation and free energy calculations. Curr. Computeraided Drug Des. 2020 16 1 17 30 10.2174/18756697OTk0jNDkgTcVY 31284868
    [Google Scholar]
  89. Rippin I. Eldar-Finkelman H. Mechanisms and therapeutic implications of gsk-3 in treating neurodegeneration. Cells 2021 10 2 262 10.3390/cells10020262 33572709
    [Google Scholar]
  90. Amaral B. Capacci A. Anderson T. Elucidation of the GSK3α structure informs the design of novel, paralog-selective inhibitors. ACS Chem. Neurosci. 2023 14 6 1080 1094 10.1021/acschemneuro.2c00476 36812145
    [Google Scholar]
  91. Kingwell K. Flipping the switch for selective GSK3 inhibition. Nat. Rev. Drug Discov. 2018 17 5 314 10.1038/nrd.2018.63 29700491
    [Google Scholar]
  92. Davies M.P. Benitez R. Perez C. Structure-Based design of potent selective nanomolar type-ii inhibitors of glycogen synthase kinase-3β. J. Med. Chem. 2021 64 3 1497 1509 10.1021/acs.jmedchem.0c01568 33499592
    [Google Scholar]
  93. Zhao J. Wei M. Guo M. GSK3: A potential target and pending issues for treatment of Alzheimer’s disease. CNS Neurosci. Ther. 2024 30 7 e14818 10.1111/cns.14818 38946682
    [Google Scholar]
  94. Jitendra J.N. Raja S.R.A. Navigating the GSK-3β inhibitors as versatile multi-target drug ligands in Alzheimer’s disease intervention - A comprehensive review. Results Chem 2024 7 101500 10.1016/j.rechem.2024.101500
    [Google Scholar]
  95. Benek O. Korabecny J. Soukup O. A perspective on multi-target drugs for Alzheimer’s disease. Trends Pharmacol. Sci. 2020 41 7 434 445 10.1016/j.tips.2020.04.008 32448557
    [Google Scholar]
  96. Cheong S.L. Tiew J.K. Fong Y.H. Current pharmacotherapy and multi-target approaches for Alzheimer’s disease. Pharmaceuticals 2022 15 12 1560 10.3390/ph15121560 36559010
    [Google Scholar]
  97. Zucchella C. Sinforiani E. Tamburin S. The multidisciplinary approach to alzheimer’s disease and dementia. a narrative review of non-pharmacological treatment. Front. Neurol. 2018 9 1058 10.3389/fneur.2018.01058 30619031
    [Google Scholar]
  98. Bajda M. Guzior N. Ignasik M. Malawska B. Multi-target-directed ligands in Alzheimer’s disease treatment. Curr. Med. Chem. 2011 18 32 4949 4975 10.2174/092986711797535245 22050745
    [Google Scholar]
  99. de Freitas Silva M. Dias K.S.T. Gontijo V.S. Ortiz C.J.C. Viegas C. Multi-target directed drugs as a modern approach for drug design towards Alzheimer’s disease: An update. Curr. Med. Chem. 2018 25 29 3491 3525 10.2174/0929867325666180111101843 29332563
    [Google Scholar]
  100. Giannoni P. Fossati S. Marcello E. Claeysen S. Editorial: Identification of multiple targets in the fight against Alzheimer’s disease. Front. Aging Neurosci. 2020 12 169 10.3389/fnagi.2020.00169 32612524
    [Google Scholar]
  101. Bolinger A.A. Zhou J. Exploring New Vista for Alzheimer’s Disease Drug Targets (Part II). Curr. Top. Med. Chem. 2023 23 13 1211 1213 10.2174/156802662313230626121232 37464550
    [Google Scholar]
  102. Chen Z.R. Huang J.B. Yang S.L. Hong F.F. Role of cholinergic signaling in Alzheimer’s disease. Molecules 2022 27 6 1816 10.3390/molecules27061816 35335180
    [Google Scholar]
  103. Hampel H. Mesulam M.M. Cuello A.C. Revisiting the cholinergic hypothesis in Alzheimer’s disease: Emerging evidence from transla-tional and clinical research. J. Prev. Alzheimers Dis. 2019 6 1 2 15 10.14283/jpad.2018.43 30569080
    [Google Scholar]
  104. Abujamai J. Satar R. Ansari S.A. Designing and formulation of nanocarriers for “alzheimer’s and parkinson’s” early detection and therapy. CNS Neurol. Disord. Drug Targets 2024 23 10 1251 1262 10.2174/0118715273297024240201055550 38351689
    [Google Scholar]
  105. Cummings J. Osse A.M.L. Cammann D. Powell J. Chen J. Anti-Amyloid monoclonal antibodies for the treatment of alzheimer’s disease. BioDrugs 2024 38 1 5 22 10.1007/s40259‑023‑00633‑2 37955845
    [Google Scholar]
  106. Satir T.M. Agholme L. Karlsson A. Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission. Alzheimers Res. Ther. 2020 12 1 63 10.1186/s13195‑020‑00635‑0 32456694
    [Google Scholar]
  107. Lauretti E. Dincer O. Praticò D. Glycogen synthase kinase-3 signaling in Alzheimer’s disease. Biochim. Biophys. Acta Mol. Cell Res. 2020 1867 5 118664 10.1016/j.bbamcr.2020.118664 32006534
    [Google Scholar]
  108. Ghosh A.K. Gemma S. Tang J. β-Secretase as a therapeutic target for Alzheimer’s disease. Neurotherapeutics 2008 5 3 399 408 10.1016/j.nurt.2008.05.007 18625451
    [Google Scholar]
  109. Cui J. Wang X. Li X. Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s disease-related pathogenesis. Cell Discov. 2015 1 1 15021 10.1038/celldisc.2015.21 27462420
    [Google Scholar]
  110. Vassar R. BACE1: The beta-secretase enzyme in Alzheimer’s disease. J. Mol. Neurosci. 2004 23 1-2 105 114 10.1385/JMN:23:1‑2:105 15126696
    [Google Scholar]
  111. Koch M.S. Deo M. Schmitt L.M. Hoetker M.S. Turcan Ş. GSK3 acts as a switch for transcriptional programs in a model of low-grade glio-magenesis. Acta Neuropathol. Commun. 2025 13 1 87 10.1186/s40478‑025‑02006‑y 40307935
    [Google Scholar]
  112. Wong S.K. Glycogen synthase kinase-3 beta (GSK3β) as a potential drug target in regulating osteoclastogenesis: An updated review on current evidence. Biomolecules 2024 14 4 502 10.3390/biom14040502 38672518
    [Google Scholar]
  113. Patel S. Doble B. Woodgett J.R. Glycogen synthase kinase-3 in insulin and Wnt signalling: A double-edged sword? Biochem. Soc. Trans. 2004 32 5 803 808 10.1042/BST0320803 15494020
    [Google Scholar]
  114. Nakamura M. Liu T. Husain S. Glycogen synthase kinase-3α promotes fatty acid uptake and lipotoxic cardiomyopathy. Cell Metab. 2019 29 5 1119 1134.e12 10.1016/j.cmet.2019.01.005 30745182
    [Google Scholar]
  115. Prajapati C. Tripathi P.N. Sood S. Intellectual property rights in neuroprotective biomaterials. In: Kumar G, Mukherjee S, Kumar S, Eds.Biomaterials and Neurodegenerative Disorders. Kumar G. Mukherjee S. Kumar S. Singapore Springer 2025 10.1007/978‑981‑97‑9959‑6_10
    [Google Scholar]
  116. Ramakrishna K. Advanced biomaterials in neuroprotection: Innovations and clinical applications. Springer Nature 2025 69 92
    [Google Scholar]
  117. Singh S. Rai S.N. Singh S.K. Synaptic plasticity in neurodegenerative disorders. 1st ed CRC Press 2024 10.1201/9781003464648
    [Google Scholar]
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Role of GSK-3 Inhibition in Alzheimer’s Disease Therapy
Bentham Science Publishers ; https://doi.org/10.2174/0115672050400781250904082943
/content/journals/car/10.2174/0115672050400781250904082943
/content/journals/car/10.2174/0115672050400781250904082943
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  • Article Type:     Review Article
Keywords: Tau phosphorylation ; GSK-3 ; treatment ; Acetylcholine ; Alzheimer’s disease

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