Triple-Target Inhibition of Cholinesterase, Amyloid Aggregation, and GSK3β to Ameliorate Cognitive Deficits and Neuropathology in the Triple-Transgenic Mouse Model of Alzheimer’s Disease

Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE. Alzheimer’s disease. Lancet 2021, 397: 1577–1590.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Collaborators G2D. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019, 18: 88–106.

Association Alzheimer’s. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement 2023, 19: 1598–1695.

Article  Google Scholar 

Asher S, Priefer R. Alzheimer’s disease failed clinical trials. Life Sci 2022, 306: 120861.

Article  CAS  PubMed  Google Scholar 

Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet 2016, 388: 505–517.

Article  CAS  PubMed  Google Scholar 

Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res 2019, 29: 787–803.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fillit H, Green A. Aducanumab and the FDA—Where are we now? Nat Rev Neurol 2021, 17: 129–130.

Article  PubMed  Google Scholar 

Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 2023, 330: 512–527.

Article  CAS  PubMed  PubMed Central  Google Scholar 

van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med 2023, 388: 9–21.

Article  PubMed  Google Scholar 

Zhang W, Xu J, Dong J, Huang Z, Cao L. Acidification deficiency of autolysosomes induces neuronal autophagic amyloid-β plaques in Alzheimer’s disease. Neurosci Bull 2023, 39: 873–876.

Article  CAS  PubMed  Google Scholar 

Hampel H, Mesulam MM, Claudio Cuello A, Farlow MR, Giacobini E, Grossberg GT, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 2018, 141: 1917–1933.

Article  PubMed  PubMed Central  Google Scholar 

De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell 2016, 164: 603–615.

Article  PubMed  Google Scholar 

Verheijen J, Sleegers K. Understanding Alzheimer disease at the interface between genetics and transcriptomics. Trends Genet 2018, 34: 434–447.

Article  CAS  PubMed  Google Scholar 

Ju Y, Tam KY. Pathological mechanisms and therapeutic strategies for Alzheimer’s disease. Neural Regen Res 2022, 17: 543–549.

Article  CAS  PubMed  Google Scholar 

Galanis C, Fellenz M, Becker D, Bold C, Lichtenthaler SF, Müller UC, et al. Amyloid-beta mediates homeostatic synaptic plasticity. J Neurosci 2021, 41: 5157–5172.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bakota L, Brandt R. Tau biology and tau-directed therapies for Alzheimer’s disease. Drugs 2016, 76: 301–313.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 2008, 104: 1433–1439.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Leroy K, Yilmaz Z, Brion JP. Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol Appl Neurobiol 2007, 33: 43–55.

Article  CAS  PubMed  Google Scholar 

Hanger DP, Anderton BH, Noble W. Tau phosphorylation: The therapeutic challenge for neurodegenerative disease. Trends Mol Med 2009, 15: 112–119.

Article  CAS  PubMed  Google Scholar 

Uemura K, Kuzuya A, Shimozono Y, Aoyagi N, Ando K, Shimohama S, et al. GSK3beta activity modifies the localization and function of presenilin 1. J Biol Chem 2007, 282: 15823–15832.

Article  CAS  PubMed  Google Scholar 

Ly PTT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, et al. Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 2013, 123: 224–235.

Article  CAS  PubMed  Google Scholar 

Lauretti E, Dincer O, Praticò D. Glycogen synthase kinase-3 signaling in Alzheimer’s disease. Biochim Biophys Acta Mol Cell Res 2020, 1867: 118664.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Terao I, Honyashiki M, Inoue T. Comparative efficacy of lithium and aducanumab for cognitive decline in patients with mild cognitive impairment or Alzheimer’s disease: A systematic review and network meta-analysis. Ageing Res Rev 2022, 81: 101709.

Article  CAS  PubMed  Google Scholar 

Cortés-Gómez MÁ, Llorens-Álvarez E, Alom J, Del Ser T, Avila J, Sáez-Valero J, et al. Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression. J Neurochem 2021, 157: 2091–2105.

Article  PubMed  Google Scholar 

Jia JP, Jia JM, Zhou WD, Xu M, Chu CB, Yan X, et al. Differential acetylcholine and choline concentrations in the cerebrospinal fluid of patients with Alzheimer’s disease and vascular dementia. Chin Med J (Engl) 2004, 117: 1161–1164.

CAS  PubMed  Google Scholar 

Marucci G, Buccioni M, Ben DD, Lambertucci C, Volpini R, Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 2021, 190: 108352.

Article  CAS  PubMed  Google Scholar 

He J, Tam KY. Dual-target inhibitors of cholinesterase and GSK-3β to modulate Alzheimer’s disease. Drug Discov Today 2024, 29: 103914.

Article  CAS  PubMed  Google Scholar 

Albertini C, Salerno A, de Sena Murteira Pinheiro P, Bolognesi ML. From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology. Med Res Rev 2021, 41: 2606–2633.

Sameem B, Saeedi M, Mahdavi M, Shafiee A. A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer’s disease. Eur J Med Chem 2017, 128: 332–345.

Article  CAS  PubMed  Google Scholar 

Kramer T, Schmidt B, Monte FL. Small-molecule inhibitors of GSK-3: Structural insights and their application to Alzheimer’s disease models. Int J Alzheimers Dis 2012, 2012: 381029.

PubMed  PubMed Central  Google Scholar 

Ellman GL, Courtney KD, Andres V, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961, 7: 88–95.

Article  CAS  PubMed  Google Scholar 

LeVine H 3rd. Thioflavine T interaction with synthetic Alzheimer’s disease beta-amyloid peptides: Detection of amyloid aggregation in solution. Protein Sci 1993, 2: 404–410.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ju Y, Chakravarty H, Tam KY. An isoquinolinium dual inhibitor of cholinesterases and amyloid β aggregation mitigates neuropathological changes in a triple-transgenic mouse model of Alzheimer’s disease. ACS Chem Neurosci 2020, 11: 3346–3357.

Article  CAS  PubMed 

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