Generic placeholder image

Mini-Reviews in Medicinal Chemistry


ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Mini-Review Article

Recent Progress in the Drug Development for the Treatment of Alzheimer’s Disease Especially on Inhibition of Amyloid-peptide Aggregation

Author(s): Yuanyuan Liu, Lin Cong, Chu Han, Bo Li* and Rongji Dai

Volume 21, Issue 8, 2021

Published on: 27 November, 2020

Page: [969 - 990] Pages: 22

DOI: 10.2174/1389557520666201127104539

Price: $65


As the world's population is aging, Alzheimer’s disease (AD) has become a big concern since AD has started affecting younger people and the population of AD patients is increasing worldwide. It has been revealed that the neuropathological hallmarks of AD are typically characterized by the presence of neurotoxic extracellular amyloid plaques in the brain, which are surrounded by tangles of neuronal fibers. However, the causes of AD have not been completely understood yet. Currently, there is no drug to effectively prevent AD or to completely reserve the symptoms in the patients. This article reviews the pathological features associated with AD, the recent progress in research on the drug development to treat AD, especially on the discovery of natural product derivatives to inhibit Aβ peptide aggregation as well as the design and synthesis of Aβ peptide aggregation inhibitors to treat AD.

Keywords: Alzheimer's disease, amyloid hypothesis, amyloid β aggregation, amyloid β peptide inhibitors, drug development, clinical trials.

« Previous
Graphical Abstract
De Strooper, B.; Karran, E. The cellular phase of Alzheimer’s disease. Cell, 2016, 164(4), 603-615.
[] [PMID: 26871627]
McDade, E.; Bateman, R.J. Stop Alzheimer’s before it starts. Nature, 2017, 547(7662), 153-155.
[] [PMID: 28703214]
Gaugler, J.; James, B.; Johnson, T.; Marin, A.; Weuve, J.; Assoc, A.s. 2019 Alzheimer’s disease facts and figures. Alzheimers Dement., 2019, 15(3), 321-387.
2020 Alzheimer’s disease facts and figures. Alzheimers Dement., 2020, 16(3), 391-460.
[] [PMID: 32157811]
Zhang, D.F.; Xu, M.; Bi, R.; Yao, Y.G. Genetic analyses of Alzheimer’s disease in China: Achievements and perspectives. ACS Chem. Neurosci., 2019, 10(2), 890-901.
[] [PMID: 30698408]
Jia, J.; Wei, C.; Chen, S.; Li, F.; Tang, Y.; Qin, W.; Zhao, L.; Jin, H.; Xu, H.; Wang, F.; Zhou, A.; Zuo, X.; Wu, L.; Han, Y.; Han, Y.; Huang, L.; Wang, Q.; Li, D.; Chu, C.; Shi, L.; Gong, M.; Du, Y.; Zhang, J.; Zhang, J.; Zhou, C.; Lv, J.; Lv, Y.; Xie, H.; Ji, Y.; Li, F.; Yu, E.; Luo, B.; Wang, Y.; Yang, S.; Qu, Q.; Guo, Q.; Liang, F.; Zhang, J.; Tan, L.; Shen, L.; Zhang, K.; Zhang, J.; Peng, D.; Tang, M.; Lv, P.; Fang, B.; Chu, L.; Jia, L.; Gauthier, S. The cost of Alzheimer’s disease in China and re-estimation of costs worldwide. Alzheimers Dement., 2018, 14(4), 483-491.
[] [PMID: 29433981]
Jia, J.; Xu, E.; Shao, Y.; Jia, J.; Sun, Y.; Li, D. One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer’s disease. J. Alzheimers Dis., 2005, 7(2), 119-124.
[] [PMID: 15851849]
Jia, L.; Quan, M.; Fu, Y.; Zhao, T.; Li, Y.; Wei, C.; Tang, Y.; Qin, Q.; Wang, F.; Qiao, Y.; Shi, S.; Wang, Y-J.; Du, Y.; Zhang, J.; Zhang, J.; Luo, B.; Qu, Q.; Zhou, C.; Gauthier, S.; Jia, J. Group for the Project of Dementia Situation in China. Dementia in China: Epidemiology, clinical management, and research advances. Lancet Neurol., 2020, 19(1), 81-92.
[] [PMID: 31494009]
Wimo, A.; Guerchet, M.; Ali, G.C.; Wu, Y.T.; Prina, A.M.; Winblad, B.; Jönsson, L.; Liu, Z.; Prince, M. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement., 2017, 13(1), 1-7.
[] [PMID: 27583652]
Wimo, A.; Jönsson, L.; Bond, J.; Prince, M.; Winblad, B.; Int, A.D. Alzheimer Disease International. The worldwide economic impact of dementia 2010. Alzheimers Dement., 2013, 9(1), 1-11.e3.
[] [PMID: 23305821]
Snyder, P.J.; Pearn, A.M. Historical note on Darwin’s consideration of early-onset dementia in older persons, thirty-six years before Alzheimer’s initial case report. Alzheimers Dement., 2007, 3(3), 137-142.
[] [PMID: 19595928]
Karran, E.; Mercken, M.; De Strooper, B. The amyloid cascade hypothesis for Alzheimer’s disease: An appraisal for the development of therapeutics. Nat. Rev. Drug Discov., 2011, 10(9), 698-712.
[] [PMID: 21852788]
Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med., 2016, 8(6), 595-608.
[] [PMID: 27025652]
Jack, C.R., Jr; Holtzman, D.M. Biomarker modeling of Alzheimer’s disease. Neuron, 2013, 80(6), 1347-1358.
[] [PMID: 24360540]
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 2002, 297(5580), 353-356.
[] [PMID: 12130773]
Szaruga, M.; Veugelen, S.; Benurwar, M.; Lismont, S.; Sepulveda-Falla, D.; Lleo, A.; Ryan, N.S.; Lashley, T.; Fox, N.C.; Murayama, S.; Gijsen, H.; De Strooper, B.; Chávez-Gutiérrez, L. Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease. J. Exp. Med., 2015, 212(12), 2003-2013.
[] [PMID: 26481686]
Selkoe, D.J. Alzheimer’s disease: Genes, proteins, and therapy. Physiol. Rev., 2001, 81(2), 741-766.
[] [PMID: 11274343]
Vergallo, A.; Mégret, L.; Lista, S.; Cavedo, E.; Zetterberg, H.; Blennow, K.; Vanmechelen, E.; De Vos, A.; Habert, M.O.; Potier, M.C.; Dubois, B.; Neri, C.; Hampel, H.; Dubois, B.; Hampel, H.; Bakardjian, H.; Benali, H.; Colliot, O.; Marie-O, H.; Lamari, F.; Mochel, F.; Potier, M.C.; de Schotten, M.T.; Afshar, M.; Aguilar, L.F.; Akman-Anderson, L.; Arenas, J.; Avila, J.; Babiloni, C.; Baldacci, F.; Batrla, R.; Benda, N.; Black, K.L.; Bokde, A.L.W.; Bonuccelli, U.; Broich, K.; Cacciola, F.; Caraci, F.; Castrillo, J.; Cavedo, E.; Ceravolo, R.; Chiesa, P.A.; Corvol, J.C.; Cuello, A.C.; Cummings, J.L.; Depypere, H.; Dubois, B.; Duggento, A.; Emanuele, E.; Escott-Price, V.; Federoff, H.; Ferretti, M.T.; Fiandaca, M.; Frank, R.A.; Garaci, F.; Geerts, H.; Giorgi, F.S.; Goetzl, E.J.; Graziani, M.; Haberkamp, M.; Habert, M.O.; Hampel, H.; Herholz, K.; Hernandez, F.; Kapogiannis, D.; Karran, E.; Kiddle, S.J.; Kim, S.H.; Koronyo, Y.; Koronyo-Hamaoui, M.; Langevin, T.; Lehericy, S.; Lucia, A.; Lista, S.; Lorenceau, J.; Mango, D.; Mapstone, M.; Neri, C.; Nistico, R.; O’Bryant, S.E.; Palmero, G.; Perry, G.; Ritchie, C.; Rossi, S.; Saidi, A.; Santarnecchi, E.; Schneider, L.S.; Sporns, O.; Toschi, N.; Verdooner, S.R.; Vergallo, A.; Villain, N.; Welikovitch, L.A.; Woodcock, J.; Younesi, E.; Grp, I-P.S. INSIGHT-preAD study group. Alzheimer Precision Medicine Initiative (APMI). Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer’s disease. Alzheimers Dement., 2019, 15(6), 764-775.
[] [PMID: 31113759]
Palop, J.J.; Mucke, L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: From synapses toward neural networks. Nat. Neurosci., 2010, 13(7), 812-818.
[] [PMID: 20581818]
Liu, X.; Zhao, X.; Zeng, X.; Bossers, K.; Swaab, D.F.; Zhao, J.; Pei, G. β-arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology. Cell Res., 2013, 23(3), 351-365.
[] [PMID: 23208420]
Jung, S.; Hyun, J.; Nah, J.; Han, J.; Kim, S-H.; Park, J.; Oh, Y.; Gwon, Y.; Moon, S.; Jo, D-G.; Jung, Y-K. SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions. Sci. Signal., 2020, 13(623)eaax8949
[] [PMID: 32184288]
Wang, R.; Zhang, Y.W.; Zhang, X.; Liu, R.; Zhang, X.; Hong, S.; Xia, K.; Xia, J.; Zhang, Z.; Xu, H. Transcriptional regulation of APH-1A and increased gamma-secretase cleavage of APP and Notch by HIF-1 and hypoxia. FASEB J., 2006, 20(8), 1275-1277.
[] [PMID: 16645044]
Dartigues, J.F.; Berr, C.; Helmer, C.; Letenneur, L. Epidemiology of Alzheimer’s disease. M S-. Med. Sci., 2002, 18(6-7), 737-743.
Yu, L.; Petyuk, V.A.; Tasaki, S.; Boyle, P.A.; Gaiteri, C.; Schneider, J.A.; De Jager, P.L.; Bennett, D.A. Association of cortical beta-amyloid protein in the absence of insoluble deposits with Alzheimer disease. JAMA Neurol., 2019, 76(7), 818-826.
[] [PMID: 31009033]
Crouch, P.J.; Savva, M.S.; Hung, L.W.; Donnelly, P.S.; Mot, A.I.; Parker, S.J.; Greenough, M.A.; Volitakis, I.; Adlard, P.A.; Cherny, R.A.; Masters, C.L.; Bush, A.I.; Barnham, K.J.; White, A.R. The Alzheimer’s therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J. Neurochem., 2011, 119(1), 220-230.
[] [PMID: 21797865]
Kimura, R.; Devi, L.; Ohno, M. Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer’s disease transgenic mice. J. Neurochem., 2010, 113(1), 248-261.
[] [PMID: 20089133]
Filser, S.; Ovsepian, S.V.; Masana, M.; Blazquez-Llorca, L.; Brandt Elvang, A.; Volbracht, C.; Müller, M.B.; Jung, C.K.E.; Herms, J. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol. Psychiatry, 2015, 77(8), 729-739.
[] [PMID: 25599931]
Cole, S.L.; Vassar, R. The Alzheimer’s disease beta-secretase enzyme, BACE1. Mol. Neurodegener., 2007, 2, 22.
[] [PMID: 18005427]
Selkoe, D.J. Presenilin, Notch, and the genesis and treatment of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2001, 98(20), 11039-11041.
[] [PMID: 11572965]
Doody, R.S.; Raman, R.; Farlow, M.; Iwatsubo, T.; Vellas, B.; Joffe, S.; Kieburtz, K.; He, F.; Sun, X.; Thomas, R.G.; Aisen, P.S.; Siemers, E.; Sethuraman, G.; Mohs, R. Alzheimer’s Disease Cooperative Study Steering Committee. Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med., 2013, 369(4), 341-350.
[] [PMID: 23883379]
Haass, C.; Schlossmacher, M.G.; Hung, A.Y.; Vigo-Pelfrey, C.; Mellon, A.; Ostaszewski, B.L.; Lieberburg, I.; Koo, E.H.; Schenk, D.; Teplow, D.B.; Selkoe, D.J. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature, 1992, 359(6393), 322-325.
[] [PMID: 1383826]
Seubert, P.; Vigo-Pelfrey, C.; Esch, F.; Lee, M.; Dovey, H.; Davis, D.; Sinha, S.; Schlossmacher, M.; Whaley, J.; Swindlehurst, C.; Mccormack, R.; Wolfert, R.; Selkoe, D.; Lieberburg, I.; Schenk, D. Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature, 1992, 359(6393), 325-327.
[] [PMID: 1406936]
Golde, T.E. Open questions for Alzheimer’s disease immunotherapy. Alzheimers Res. Ther., 2014, 6(1), 3.
[] [PMID: 24393284]
Coric, V.; van Dyck, C.H.; Salloway, S.; Andreasen, N.; Brody, M.; Richter, R.W.; Soininen, H.; Thein, S.; Shiovitz, T.; Pilcher, G.; Colby, S.; Rollin, L.; Dockens, R.; Pachai, C.; Portelius, E.; Andreasson, U.; Blennow, K.; Soares, H.; Albright, C.; Feldman, H.H.; Berman, R.M. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol., 2012, 69(11), 1430-1440.
[] [PMID: 22892585]
Green, R.C.; Schneider, L.S.; Amato, D.A.; Beelen, A.P.; Wilcock, G.; Swabb, E.A.; Zavitz, K.H. Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA, 2009, 302(23), 2557-2564.
[] [PMID: 20009055]
Egan, M.F.; Kost, J.; Tariot, P.N.; Aisen, P.S.; Cummings, J.L.; Vellas, B.; Sur, C.; Mukai, Y.; Voss, T.; Furtek, C.; Mahoney, E.; Harper Mozley, L.; Vandenberghe, R.; Mo, Y.; Michelson, D. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med., 2018, 378(18), 1691-1703.
[] [PMID: 29719179]
Evin, G. Future therapeutics in Alzheimer’s disease: Development status of BACE inhibitors. BioDrugs, 2016, 30(3), 173-194.
[] [PMID: 27023706]
Honig, L.S.; Vellas, B.; Woodward, M.; Boada, M.; Bullock, R.; Borrie, M.; Hager, K.; Andreasen, N.; Scarpini, E.; Liu-Seifert, H.; Case, M.; Dean, R.A.; Hake, A.; Sundell, K.; Poole Hoffmann, V.; Carlson, C.; Khanna, R.; Mintun, M.; DeMattos, R.; Selzler, K.J.; Siemers, E. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med., 2018, 378(4), 321-330.
[] [PMID: 29365294]
Ostrowitzki, S.; Lasser, R.A.; Dorflinger, E.; Scheltens, P.; Barkhof, F.; Nikolcheva, T.; Ashford, E.; Retout, S.; Hofmann, C.; Delmar, P.; Klein, G.; Andjelkovic, M.; Dubois, B.; Boada, M.; Blennow, K.; Santarelli, L.; Fontoura, P. SCarlet RoAD Investigators. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res. Ther., 2017, 9(1), 95.
[] [PMID: 29221491]
Blennow, K.; Zetterberg, H. The past and the future of Alzheimer’s disease CSF biomarkers-a journey toward validated biochemical tests covering the whole spectrum of molecular events. Front. Neurosci., 2015, 9, 345-345.
[] [PMID: 26483625]
Lee, V.M.Y.; Goedert, M.; Trojanowski, J.Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci., 2001, 24, 1121-1159.
[] [PMID: 11520930]
Morris, M.; Maeda, S.; Vossel, K.; Mucke, L. The many faces of tau. Neuron, 2011, 70(3), 410-426.
[] [PMID: 21555069]
Min, S.W.; Cho, S.H.; Zhou, Y.G.; Schroeder, S.; Haroutunian, V.; Seeley, W.W.; Huang, E.J.; Shen, Y.; Masliah, E.; Mukherjee, C.; Meyers, D.; Cole, P.A.; Ott, M.; Gan, L. Acetylation of Tau inhibits its degradation and contributes to tauopathy. Neuron, 2010, 68(4), 801-801.
Lee, V.M.Y.; Trojanowski, J.Q. Hot papers - Neuroscience Alzheimer’s disease research - Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau by E.S. Matsuo, R.-W. Shin, M.L. Billingsley, A.V. deVoorde, M. O’Connor, J.Q. Trojanowski, V.M.-Y. Lee - Comments. Scientist, 1996, 10(4), 13-13.
Shafiei, S.S.; Guerrero-Muñoz, M.J.; Castillo-Carranza, D.L. Tau oligomers: Cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci., 2017, 9, 83.
[] [PMID: 28420982]
Schneider, A.; Biernat, J.; von Bergen, M.; Mandelkow, E.; Mandelkow, E.M. Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry, 1999, 38(12), 3549-3558.
[] [PMID: 10090741]
Wang, J.Z.; Grundke-Iqbal, I.; Iqbal, K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur. J. Neurosci., 2007, 25(1), 59-68.
[] [PMID: 17241267]
Alonso, A.C.; Grundke-Iqbal, I.; Iqbal, K. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med., 1996, 2(7), 783-787.
[] [PMID: 8673924]
Taniguchi, S.; Suzuki, N.; Masuda, M.; Hisanaga, S.; Iwatsubo, T.; Goedert, M.; Hasegawa, M. Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J. Biol. Chem., 2005, 280(9), 7614-7623.
[] [PMID: 15611092]
Areche, C.; Zapata, F.; González, M.; Díaz, E.; Montecinos, R.; Hernández, M.; Melo, F.; Cornejo, A. Anthraquinone derivative reduces tau oligomer progression by inhibiting cysteine-cysteine interaction. Chem. Open, 2019, 8(5), 554-559.
[] [PMID: 31065505]
Akoury, E.; Pickhardt, M.; Gajda, M.; Biernat, J.; Mandelkow, E.; Zweckstetter, M. Mechanistic basis of phenothiazine-driven inhibition of Tau aggregation. Angew. Chem. Int. Ed. Engl., 2013, 52(12), 3511-3515.
[] [PMID: 23401175]
Soeda, Y.; Saito, M.; Maeda, S.; Ishida, K.; Nakamura, A.; Kojima, S.; Takashima, A. Methylene blue inhibits formation of Tau fibrils but not of granular Tau oligomers: A plausible key to understanding failure of a clinical trial for Alzheimer’s disease. J. Alzheimers Dis., 2019, 68(4), 1677-1686.
[] [PMID: 30909223]
Traynelis, S.F.; Wollmuth, L.P.; McBain, C.J.; Menniti, F.S.; Vance, K.M.; Ogden, K.K.; Hansen, K.B.; Yuan, H.; Myers, S.J.; Dingledine, R. Glutamate receptor ion channels: Structure, regulation, and function. Pharmacol. Rev., 2010, 62(3), 405-496.
[] [PMID: 20716669]
Mota, S.I.; Ferreira, I.L.; Rego, A.C. Dysfunctional synapse in Alzheimer’s disease - A focus on NMDA receptors. Neuropharmacology, 2014, 76(Pt A), 16-26.
[] [PMID: 23973316]
Wang, R.; Reddy, P.H. Role of glutamate and NMDA receptors in Alzheimer’s disease. J. Alzheimers Dis., 2017, 57(4), 1041-1048.
[] [PMID: 27662322]
Liu, P.P.; Xie, Y.; Meng, X.Y.; Kang, J.S. History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct. Target. Ther., 2019, 4, 29.
Giacobini, E. Therapy of Alzheimer’s disease reducing beta-A: Now and the future. Eur. Neuropsychopharmacol., 2002, 12, S135-S135.
Peauger, L.; Azzouz, R.; Gembus, V.; Ţînţaş, M.L.; Sopková-de Oliveira Santos, J.; Bohn, P.; Papamicaël, C.; Levacher, V. Donepezil-based central acetylcholinesterase inhibitors by means of a “bio-oxidizable” prodrug strategy: Design, synthesis, and in vitro biological evaluation. J. Med. Chem., 2017, 60(13), 5909-5926.
[] [PMID: 28613859]
Dolles, D.; Hoffmann, M.; Gunesch, S.; Marinelli, O.; Möller, J.; Santoni, G.; Chatonnet, A.; Lohse, M.J.; Wittmann, H.J.; Strasser, A.; Nabissi, M.; Maurice, T.; Decker, M. Structure-activity relationships and computational investigations into the development of potent and balanced dual-acting butyrylcholinesterase inhibitors and human cannabinoid receptor 2 ligands with pro-cognitive in vivo profiles. J. Med. Chem., 2018, 61(4), 1646-1663.
[] [PMID: 29400965]
Dighe, S.N.; Deora, G.S.; De la Mora, E.; Nachon, F.; Chan, S.; Parat, M.O.; Brazzolotto, X.; Ross, B.P. Discovery and structure-activity relationships of a highly selective butyrylcholinesterase inhibitor by structure-based virtual screening. J. Med. Chem., 2016, 59(16), 7683-7689.
[] [PMID: 27405689]
Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol., 2018, 14, 450-464.
[] [PMID: 29080524]
Butterfield, D.A.; Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci., 2019, 20(3), 148-160.
[] [PMID: 30737462]
Gu, F.; Zhu, M.; Shi, J.; Hu, Y.; Zhao, Z. Enhanced oxidative stress is an early event during development of Alzheimer-like pathologies in presenilin conditional knock-out mice. Neurosci. Lett., 2008, 440(1), 44-48.
[] [PMID: 18539391]
Butterfield, D.A. The 2013 SFRBM discovery award: Selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment. Free Radic. Biol. Med., 2014, 74, 157-174.
[] [PMID: 24996204]
Chen, L.; Na, R.; Gu, M.; Richardson, A.; Ran, Q. Lipid peroxidation up-regulates BACE1 expression in vivo: A possible early event of amyloidogenesis in Alzheimer’s disease. J. Neurochem., 2008, 107(1), 197-207.
[] [PMID: 18680556]
Butterfield, D.A.; Castegna, A.; Lauderback, C.M.; Drake, J. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol. Aging, 2002, 23(5), 655-664.
[] [PMID: 12392766]
Rojas, C.; Rojas-Castaneda, J.; Rojas, P. Antioxidant properties of a ginkgo biloba leaf extract (egb 761) in animal models of Alzheimer’s and Parkinson’s diseases. Curr. Top. Nutraceutical Res., 2016, 14(1), 1-16.
Hambright, W.S.; Fonseca, R.S.; Chen, L.; Na, R.; Ran, Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol., 2017, 12, 8-17.
[] [PMID: 28212525]
Zhang, Y.H.; Wang, D.W.; Xu, S.F.; Zhang, S.; Fan, Y.G.; Yang, Y.Y.; Guo, S.Q.; Wang, S.; Guo, T.; Wang, Z.Y.; Guo, C. α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. Redox Biol., 2018, 14, 535-548.
[] [PMID: 29126071]
Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; Morrison, B., III; Stockwell, B.R. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5), 1060-1072.
[] [PMID: 22632970]
Angeli, J.P.F.; Shah, R.; Pratt, D.A.; Conrad, M. Ferroptosis inhibition: Mechanisms and opportunities. Trends Pharmacol. Sci., 2017, 38(5), 489-498.
[] [PMID: 28363764]
Stockwell, B.R.; Friedmann Angeli, J.P.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascón, S.; Hatzios, S.K.; Kagan, V.E.; Noel, K.; Jiang, X.; Linkermann, A.; Murphy, M.E.; Overholtzer, M.; Oyagi, A.; Pagnussat, G.C.; Park, J.; Ran, Q.; Rosenfeld, C.S.; Salnikow, K.; Tang, D.; Torti, F.M.; Torti, S.V.; Toyokuni, S.; Woerpel, K.A.; Zhang, D.D. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2), 273-285.
[] [PMID: 28985560]
R., Cardoso B.; Hare, D.J.; Lind, M.; McLean, C.A.; Volitakis, I.; Laws, S.M.; Masters, C.L.; Bush, A.I.; Roberts, B.R. The APOE epsilon 4 allele is associated with lower selenium levels in the brain: Implications for Alzheimer’s disease. ACS Chem. Neurosci., 2017, 8(7), 1459-1464.
[] [PMID: 28453930]
Chen, L.; Hambright, W.S.; Na, R.; Ran, Q. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J. Biol. Chem., 2015, 290(47), 28097-28106.
[] [PMID: 26400084]
Birch, A.M.; Katsouri, L.; Sastre, M. Modulation of inflammation in transgenic models of Alzheimer’s disease; J. Neuroinflamm, 2014, p. 11.
Wyss-Coray, T. Inflammation in Alzheimer disease: Driving force, bystander or beneficial response? Nat. Med., 2006, 12(9), 1005-1015.
[PMID: 16960575]
Guillot-Sestier, M.V.; Doty, K.R.; Gate, D.; Rodriguez, J., Jr; Leung, B.P.; Rezai-Zadeh, K.; Town, T. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron, 2015, 85(3), 534-548.
[] [PMID: 25619654]
Chakrabarty, P.; Ceballos-Diaz, C.; Beccard, A.; Janus, C.; Dickson, D.; Golde, T.E.; Das, P. IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J. Immunol., 2010, 184(9), 5333-5343.
[] [PMID: 20368278]
Hermine, O. Masitinib for the treatment of Alzheimer’s disease: Clinical and preclinical data. Neurobiol. Aging, 2016, 39, S4-S5.
Folch, J.; Petrov, D.; Ettcheto, M.; Pedrós, I.; Abad, S.; Beas-Zarate, C.; Lazarowski, A.; Marin, M.; Olloquequi, J.; Auladell, C.; Camins, A. Masitinib for the treatment of mild to moderate Alzheimer’s disease. Expert Rev. Neurother., 2015, 15(6), 587-596.
[] [PMID: 25961655]
North, R.A. Molecular physiology of P2X receptors. Physiol. Rev., 2002, 82(4), 1013-1067.
[] [PMID: 12270951]
Khakh, B.S. Molecular physiology of P2X receptors and ATP signalling at synapses. Nat. Rev. Neurosci., 2001, 2(3), 165-174.
[] [PMID: 11256077]
Surprenant, A.; Rassendren, F.; Kawashima, E.; North, R.A.; Buell, G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science, 1996, 272(5262), 735-738.
[] [PMID: 8614837]
North, R.A. P2X receptors. Philos. T. R. Soc. B., 1700, 2016, 371.
Khakh, B.S.; Bao, X.R.; Labarca, C.; Lester, H.A. Neuronal P2X transmitter-gated cation channels change their ion selectivity in seconds. Nat. Neurosci., 1999, 2(4), 322-330.
[] [PMID: 10204538]
Parvathenani, L.K.; Tertyshnikova, S.; Greco, C.R.; Roberts, S.B.; Robertson, B.; Posmantur, R. P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease. J. Biol. Chem., 2003, 278(15), 13309-13317.
[] [PMID: 12551918]
Ryu, J.K.; McLarnon, J.G. Block of purinergic P2X(7) receptor is neuroprotective in an animal model of Alzheimer’s disease. Neuroreport, 2008, 19(17), 1715-1719.
[] [PMID: 18852683]
Machado, V.; Zöller, T.; Attaai, A.; Spittau, B. Microglia-mediated neuroinflammation and neurotrophic factor-induced protection in the MPTP mouse model of Parkinson’s Disease-lessons from transgenic mice. Int. J. Mol. Sci., 2016, 17(2)E151
[] [PMID: 26821015]
Aktas, O.; Ullrich, O.; Infante-Duarte, C.; Nitsch, R.; Zipp, F. Neuronal damage in brain inflammation. Arch. Neurol., 2007, 64(2), 185-189.
[] [PMID: 17296833]
Heckmann, B.L.; Teubner, B.J.W.; Tummers, B.; Boada-Romero, E.; Harris, L.; Yang, M.; Guy, C.S.; Zakharenko, S.S.; Green, D.R. LC3-associated endocytosis facilitates beta-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell, 2019, 178(3), 536-551.
[] [PMID: 31257024]
Lipinski, M.M.; Zheng, B.; Lu, T.; Yan, Z.; Py, B.F.; Ng, A.; Xavier, R.J.; Li, C.; Yankner, B.A.; Scherzer, C.R.; Yuan, J. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2010, 107(32), 14164-14169.
[] [PMID: 20660724]
Huang, Y.; Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell, 2012, 148(6), 1204-1222.
[] [PMID: 22424230]
Mahley, R.W.; Weisgraber, K.H.; Huang, Y. Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2006, 103(15), 5644-5651.
[] [PMID: 16567625]
Safieh, M.; Korczyn, A.D.; Michaelson, D.M. ApoE4: An emerging therapeutic target for Alzheimer’s disease. BMC Med., 2019, 17(1), 64.
[] [PMID: 30890171]
Belloy, M.E.; Napolioni, V.; Greicius, M.D. A quarter century of APOE and Alzheimer’s disease: Progress to date and the path forward. Neuron, 2019, 101(5), 820-838.
[] [PMID: 30844401]
Zhao, N.; Liu, C.C.; Qiao, W.; Bu, G.; Apolipoprotein, E. receptors, and modulation of Alzheimer’s disease. Biol. Psychiatry, 2018, 83(4), 347-357.
[] [PMID: 28434655]
Chen, H.K.; Liu, Z.; Meyer-Franke, A.; Brodbeck, J.; Miranda, R.D.; McGuire, J.G.; Pleiss, M.A.; Ji, Z.S.; Balestra, M.E.; Walker, D.W.; Xu, Q.; Jeong, D.E.; Budamagunta, M.S.; Voss, J.C.; Freedman, S.B.; Weisgraber, K.H.; Huang, Y.; Mahley, R.W. Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J. Biol. Chem., 2012, 287(8), 5253-5266.
[] [PMID: 22158868]
Mecca, A.P.; Chen, M.K.; Naganawa, M.; Finnema, S.J.; Toyonaga, T.; Lin, S.F.; McDonald, J.W.; Michalak, H.R.; Nahulsi, N.B.; Huang, Y.Y.; Arnsten, A.F.; Carson, R.E.; van Dyck, C.H. Initial experience with PET imaging of synaptic density (SV2A) in Alzheimer’s disease: a new biomarker for clinical trials? Am. J. Geriatr. Psychiatry, 2018, 26(3), S145-S146.
Cummings, J.; Lee, G.; Ritter, A.; Sabbagh, M.; Zhong, K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. (N. Y.), 2019, 5, 272-293.
[] [PMID: 31334330]
Rodda, J.; Carter, J. Cholinesterase inhibitors and memantine for symptomatic treatment of dementia. BMJ, 2012, 344e2986
[] [PMID: 22550350]
Viayna, E.; Sola, I.; Bartolini, M.; De Simone, A.; Tapia-Rojas, C.; Serrano, F.G.; Sabaté, R.; Juárez-Jiménez, J.; Pérez, B.; Luque, F.J.; Andrisano, V.; Clos, M.V.; Inestrosa, N.C.; Muñoz-Torrero, D. Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents. J. Med. Chem., 2014, 57(6), 2549-2567.
[] [PMID: 24568372]
Liu, J.; Chang, L.; Song, Y.; Li, H.; Wu, Y. The role of NMDA receptors in Alzheimer’s disease. Front. Neurosci., 2019, 13, 43.
[] [PMID: 30800052]
Wilkinson, D.; Fox, N.C.; Barkhof, F.; Phul, R.; Lemming, O.; Scheltens, P.; Investigators, S. Memantine and brain atrophy in Alzheimer’s disease: A 1-year randomized controlled trial. J. Alzheimers Dis., 2012, 29(2), 459-469.
[] [PMID: 22269160]
Wang, X.; Sun, G.; Feng, T.; Zhang, J.; Huang, X.; Wang, T.; Xie, Z.; Chu, X.; Yang, J.; Wang, H.; Chang, S.; Gong, Y.; Ruan, L.; Zhang, G.; Yan, S.; Lian, W.; Du, C.; Yang, D.; Zhang, Q.; Lin, F.; Liu, J.; Zhang, H.; Ge, C.; Xiao, S.; Ding, J.; Geng, M. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res., 2019, 29(10), 787-803.
[] [PMID: 31488882]
Jiang, R.W.; Du, X.G.; Zhang, X.; Wang, X.; Hu, D.Y.; Meng, T.; Chen, Y.L.; Geng, M.Y.; Shen, J.K. Synthesis and bioassay of β-(1,4)-D-mannans as potential agents against Alzheimer’s disease. Acta Pharmacol. Sin., 2013, 34(12), 1585-1591.
[] [PMID: 24241344]
Berti, V.; Walters, M.; Sterling, J.; Quinn, C.G.; Logue, M.; Andrews, R.; Matthews, D.C.; Osorio, R.S.; Pupi, A.; Vallabhajosula, S.; Isaacson, R.S.; de Leon, M.J.; Mosconi, L. Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology, 2018, 90(20), e1789-e1798.
[] [PMID: 29653991]
Safouris, A.; Tsivgoulis, G.; Sergentanis, T.N.; Psaltopoulou, T. Mediterranean diet and risk of dementia. Curr. Alzheimer Res., 2015, 12(8), 736-744.
[] [PMID: 26159192]
McLaurin, J.; Franklin, T.; Chakrabartty, A.; Fraser, P.E. Phosphatidylinositol and inositol involvement in Alzheimer amyloid-beta fibril growth and arrest. J. Mol. Biol., 1998, 278(1), 183-194.
[] [PMID: 9571042]
Gervais, F.; Paquette, J.; Morissette, C.; Krzywkowski, P.; Yu, M.; Azzi, M.; Lacombe, D.; Kong, X.; Aman, A.; Laurin, J.; Szarek, W.A.; Tremblay, P. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol. Aging, 2007, 28(4), 537-547.
[] [PMID: 16675063]
McLaurin, J.; Kierstead, M.E.; Brown, M.E.; Hawkes, C.A.; Lambermon, M.H.L.; Phinney, A.L.; Darabie, A.A.; Cousins, J.E.; French, J.E.; Lan, M.F.; Chen, F.; Wong, S.S.N.; Mount, H.T.J.; Fraser, P.E.; Westaway, D.; St George-Hyslop, P. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat. Med., 2006, 12(7), 801-808.
[] [PMID: 16767098]
Rezai-Zadeh, K.; Shytle, D.; Sun, N.; Mori, T.; Hou, H.; Jeanniton, D.; Ehrhart, J.; Townsend, K.; Zeng, J.; Morgan, D.; Hardy, J.; Town, T.; Tan, J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J. Neurosci., 2005, 25(38), 8807-8814.
[] [PMID: 16177050]
Ehrnhoefer, D.E.; Bieschke, J.; Boeddrich, A.; Herbst, M.; Masino, L.; Lurz, R.; Engemann, S.; Pastore, A.; Wanker, E.E. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat. Struct. Mol. Biol., 2008, 15(6), 558-566.
[] [PMID: 18511942]
Wang, S.H.; Liu, F.F.; Dong, X.Y.; Sun, Y. Thermodynamic analysis of the molecular interactions between amyloid beta-peptide 42 and (-)-epigallocatechin-3-gallate. J. Phys. Chem. B, 2010, 114(35), 11576-11583.
[] [PMID: 20718413]
Wang, S.H.; Dong, X.Y.; Sun, Y. Investigation into the mechanism of (-)-epigallocatechin-3-gallate-induced precipitation of insulin. Int. J. Biol. Macromol., 2012, 50(5), 1229-1237.
[] [PMID: 22537475]
Ganguli, M.; Chandra, V.; Kamboh, M.I.; Johnston, J.M.; Dodge, H.H.; Thelma, B.K.; Juyal, R.C.; Pandav, R.; Belle, S.H.; DeKosky, S.T. Apolipoprotein E polymorphism and Alzheimer disease - The Indo-US cross-national dementia study. Arch. Neurol., 2000, 57(6), 824-830.
[] [PMID: 10867779]
Ng, T.P.; Chiam, P.C.; Lee, T.; Chua, H.C.; Lim, L.; Kua, E.H. Curry consumption and cognitive function in the elderly. Am. J. Epidemiol., 2006, 164(9), 898-906.
[] [PMID: 16870699]
Yang, F.; Lim, G.P.; Begum, A.N.; Ubeda, O.J.; Simmons, M.R.; Ambegaokar, S.S.; Chen, P.P.; Kayed, R.; Glabe, C.G.; Frautschy, S.A.; Cole, G.M. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem., 2005, 280(7), 5892-5901.
[] [PMID: 15590663]
Daval, M.; Bedrood, S.; Gurlo, T.; Huang, C.J.; Costes, S.; Butler, P.C.; Langen, R. The effect of curcumin on human islet amyloid polypeptide misfolding and toxicity. Amyloid, 2010, 17(3-4), 118-128.
[] [PMID: 21067307]
Baur, J.A.; Sinclair, D.A. Therapeutic potential of resveratrol: The in vivo evidence. Nat. Rev. Drug Discov., 2006, 5(6), 493-506.
[] [PMID: 16732220]
Porquet, D.; Griñán-Ferré, C.; Ferrer, I.; Camins, A.; Sanfeliu, C.; Del Valle, J.; Pallàs, M. Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer’s disease. J. Alzheimers Dis., 2014, 42(4), 1209-1220.
[] [PMID: 25024312]
Drygalski, K.; Fereniec, E.; Koryciński, K.; Chomentowski, A.; Kiełczewska, A.; Odrzygóźdź, C.; Modzelewska, B. Resveratrol and Alzheimer’s disease. From molecular pathophysiology to clinical trials. Exp. Gerontol., 2018, 113, 36-47.
[] [PMID: 30266470]
Sawda, C.; Moussa, C.; Turner, R.S. Resveratrol for Alzheimer’s disease. Ann. N. Y. Acad. Sci., 2017, 1403(1), 142-149.
[] [PMID: 28815614]
Ahmed, T.; Javed, S.; Javed, S.; Tariq, A.; Šamec, D.; Tejada, S.; Nabavi, S.F.; Braidy, N.; Nabavi, S.M. Resveratrol and Alzheimer’s disease: Mechanistic insights. Mol. Neurobiol., 2017, 54(4), 2622-2635.
[] [PMID: 26993301]
Gauci, A.J.; Caruana, M.; Giese, A.; Scerri, C.; Vassallo, N. Identification of polyphenolic compounds and black tea extract as potent inhibitors of lipid membrane destabilization by Aβ42 aggregates. J. Alzheimers Dis., 2011, 27(4), 767-779.
[] [PMID: 21891862]
Zhao, L.; Wang, J.L.; Liu, R.; Li, X.X.; Li, J.F.; Zhang, L. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model. Molecules, 2013, 18(8), 9949-9965.
[] [PMID: 23966081]
Chen, C.; Li, X.; Gao, P.; Tu, Y.; Zhao, M.; Li, J.; Zhang, S.; Liang, H. Baicalin attenuates alzheimer-like pathological changes and memory deficits induced by amyloid β1-42 protein. Metab. Brain Dis., 2015, 30(2), 537-544.
[] [PMID: 25108596]
Yin, F.; Liu, J.; Ji, X.; Wang, Y.; Zidichouski, J.; Zhang, J. Baicalin prevents the production of hydrogen peroxide and oxidative stress induced by Aβ aggregation in SH-SY5Y cells. Neurosci. Lett., 2011, 492(2), 76-79.
[] [PMID: 21276834]
Song, S.M.; Wang, Y.X.; Xiong, L.M.; Qu, L.B.; Xu, M.T. AFM and fluorescence spectrascopy investigation for disaggregation of existing A beta fibrils by baicalein. Chin. Chem. Lett., 2012, 23(5), 595-598.
Mori, Y.; Kato, S.; Fujisawa, Y.; Ohnishi, S.; Hiraku, Y.; Kawanishi, S.; Murata, M.; Oikawa, S. Mechanisms of DNA damage induced by morin, an inhibitor of amyloid β-peptide aggregation. Free Radic. Res., 2019, 53(1), 115-123.
[] [PMID: 30572734]
Noor, H.; Cao, P.; Raleigh, D.P. Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers. Protein Sci., 2012, 21(3), 373-382.
[] [PMID: 22238175]
Boopathi, S.; Kolandaivel, P. Targeted studies on the interaction of nicotine and morin molecules with amyloid β-protein. J. Mol. Model., 2014, 20(3), 2109.
[] [PMID: 24567151]
Siddique, Y.H.; Ali, F. Protective effect of nordihydroguaiaretic acid (NDGA) on the transgenic Drosophila model of Alzheimer’s disease. Chem. Biol. Interact., 2017, 269, 59-66.
[] [PMID: 28392391]
Ono, K.; Hasegawa, K.; Yoshiike, Y.; Takashima, A.; Yamada, M.; Naiki, H. Nordihydroguaiaretic acid potently breaks down pre-formed Alzheimer’s beta-amyloid fibrils in vitro. J. Neurochem., 2002, 81(3), 434-440.
[] [PMID: 12065652]
Stefani, M.; Rigacci, S. Beneficial properties of natural phenols: Highlight on protection against pathological conditions associated with amyloid aggregation. Biofactors, 2014, 40(5), 482-493.
[] [PMID: 24890399]
Rigacci, S.; Guidotti, V.; Bucciantini, M.; Nichino, D.; Relini, A.; Berti, A.; Stefani, M. Aβ(1-42) aggregates into non-toxic amyloid assemblies in the presence of the natural polyphenol oleuropein aglycon. Curr. Alzheimer Res., 2011, 8(8), 841-852.
[] [PMID: 21592051]
Grossi, C.; Rigacci, S.; Ambrosini, S.; Ed Dami, T.; Luccarini, I.; Traini, C.; Failli, P.; Berti, A.; Casamenti, F.; Stefani, M. The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology. PLoS One, 2013, 8(8)e71702
[] [PMID: 23951225]
Diomede, L.; Rigacci, S.; Romeo, M.; Stefani, M.; Salmona, M. Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit. PLoS One, 2013, 8(3)e58893
[] [PMID: 23520540]
Cordero, J.G.; García-Escudero, R.; Avila, J.; Gargini, R.; García-Escudero, V. Benefit of oleuropein aglycone for Alzheimer’s disease by promoting autophagy. Oxid. Med. Cell. Longev., 2018, 20185010741
[] [PMID: 29675133]
Martorell, M.; Forman, K.; Castro, N.; Capó, X.; Tejada, S.; Sureda, A. Potential therapeutic effects of oleuropein aglycone in Alzheimer’s disease. Curr. Pharm. Biotechnol., 2016, 17(11), 994-1001.
[] [PMID: 27455905]
Braidy, N.; Jugder, B.E.; Poljak, A.; Jayasena, T.; Nabavi, S.M.; Sachdev, P.; Grant, R. Molecular targets of tannic acid in Alzheimer’s disease. Curr. Alzheimer Res., 2017, 14(8), 861-869.
[] [PMID: 28176625]
Ono, K.; Hasegawa, K.; Naiki, H.; Yamada, M. Anti-amyloidogenic activity of tannic acid and its activity to destabilize Alzheimer’s beta-amyloid fibrils in vitro. Biochim. Biophys. Acta, 2004, 1690(3), 193-202.
[] [PMID: 15511626]
Sylla, T.; Pouységu, L.; Da Costa, G.; Deffieux, D.; Monti, J.P.; Quideau, S. Gallotannins and tannic acid: First chemical syntheses and in vitro inhibitory activity on Alzheimer’s amyloid -peptide aggregation. Angew. Chem. Int. Ed. Engl., 2015, 54(28), 8217-8221.
[] [PMID: 26013280]
Mori, T.; Rezai-Zadeh, K.; Koyama, N.; Arendash, G.W.; Yamaguchi, H.; Kakuda, N.; Horikoshi-Sakuraba, Y.; Tan, J.; Town, T. Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J. Biol. Chem., 2012, 287(9), 6912-6927.
[] [PMID: 22219198]
Shanmuganathan, B.; Suryanarayanan, V.; Sathya, S.; Narenkumar, M.; Singh, S.K.; Ruckmani, K.; Pandima Devi, K. Anti-amyloidogenic and anti-apoptotic effect of α-bisabolol against Aβ induced neurotoxicity in PC12 cells. Eur. J. Med. Chem., 2018, 143, 1196-1207.
[] [PMID: 29150331]
Zhao, P.; Lou, L.L.; Zhang, H.; Guo, R.; Wang, X.B.; Huang, X.X.; Song, S.J. A new dineolignan with anti-β-amyloid aggregation activity from the fruits of crataegus pinnatifida bge. Nat. Prod. Res., 2019, 1-4.
[] [PMID: 31429298]
Wang, Y.X.; Lin, B.; Zhou, L.; Yan, Z.Y.; Zhang, H.; Huang, X.X.; Song, S.J. Anti-β-amyloid aggregation activity of enantiomeric furolactone-type lignans from Archidendron clypearia (Jack) I.C.N. Nat. Prod. Res., 2020, 34(4), 456-463.
[] [PMID: 30445834]
Wang, Y.X.; Duan, Z.K.; Chang, Y.; Yan, Z.Y.; Wang, X.B.; Huang, X.X.; Song, S.J. Triterpenes from Archidendron clypearia (Jack) ICN with anti-beta-amyloid aggregation activity. Nat. Prod. Res., 2019.
Tu, L.H.; Tseng, N.H.; Tsai, Y.R.; Lin, T.W.; Lo, Y.W.; Charng, J.L.; Hsu, H.T.; Chen, Y.S.; Chen, R.J.; Wu, Y.T.; Chan, Y.T.; Chen, C.S.; Fang, J.M.; Chen, Y.R. Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity. Eur. J. Med. Chem., 2018, 158, 393-404.
[] [PMID: 30227353]
Wang, W.; Wang, W.; Yao, G.; Ren, Q.; Wang, D.; Wang, Z.; Liu, P.; Gao, P.; Zhang, Y.; Wang, S.; Song, S. Novel sarsasapogenin-triazolyl hybrids as potential anti-Alzheimer’s agents: Design, synthesis and biological evaluation. Eur. J. Med. Chem., 2018, 151, 351-362.
[] [PMID: 29635167]
Kroth, H.; Sreenivasachary, N.; Hamel, A.; Benderitter, P.; Varisco, Y.; Giriens, V.; Paganetti, P.; Froestl, W.; Pfeifer, A.; Muhs, A. Synthesis and structure-activity relationship of 2,6-disubstituted pyridine derivatives as inhibitors of β-amyloid-42 aggregation. Bioorg. Med. Chem. Lett., 2016, 26(14), 3330-3335.
[] [PMID: 27256911]
Kroth, H.; Ansaloni, A.; Varisco, Y.; Jan, A.; Sreenivasachary, N.; Rezaei-Ghaleh, N.; Giriens, V.; Lohmann, S.; López-Deber, M.P.; Adolfsson, O.; Pihlgren, M.; Paganetti, P.; Froestl, W.; Nagel-Steger, L.; Willbold, D.; Schrader, T.; Zweckstetter, M.; Pfeifer, A.; Lashuel, H.A.; Muhs, A. Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation. J. Biol. Chem., 2012, 287(41), 34786-34800.
[] [PMID: 22891248]
Sreenivasachary, N.; Lopez-Deber, P.; Kroth, H.; Lohamann, S.; Froestl, W.; Adolfsson, O.; Varisco, Y.; Giriens, V.; Paganetti, P.; Pihlgren, M.; Nagel-Steger, L.; Schrader, T.; Pfeifer, A.; Muhs, A. Discovery and structure activity relationship of small molecule inhibitors of toxic Abetal-42 oligomerization; Abstr. Pap. Am. Chem. S, 2011, p. 241.
Ha, H.J.; Kang, D.W.; Kim, H.M.; Kang, J.M.; Ann, J.; Hyun, H.J.; Lee, J.H.; Kim, S.H.; Kim, H.; Choi, K.; Hong, H.S.; Kim, Y.; Jo, D.G.; Lee, J.; Lee, J. Discovery of an orally bioavailable benzofuran analogue that serves as a beta-amyloid aggregation inhibitor for the potential treatment of Alzheimer’s disease. J. Med. Chem., 2018, 61(1), 396-402.
[] [PMID: 29161514]
Nepovimova, E.; Uliassi, E.; Korabecny, J.; Peña-Altamira, L.E.; Samez, S.; Pesaresi, A.; Garcia, G.E.; Bartolini, M.; Andrisano, V.; Bergamini, C.; Fato, R.; Lamba, D.; Roberti, M.; Kuca, K.; Monti, B.; Bolognesi, M.L. Multitarget drug design strategy: Quinone-tacrine hybrids designed to block amyloid-β aggregation and to exert anticholinesterase and antioxidant effects. J. Med. Chem., 2014, 57(20), 8576-8589.
[] [PMID: 25259726]
Cen, J.; Guo, H.; Hong, C.; Lv, J.; Yang, Y.; Wang, T.; Fang, D.; Luo, W.; Wang, C. Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity. Eur. J. Med. Chem., 2018, 144, 128-136.
[] [PMID: 29268129]
Wang, X.Q.; Xia, C.L.; Chen, S.B.; Tan, J.H.; Ou, T.M.; Huang, S.L.; Li, D.; Gu, L.Q.; Huang, Z.S. Design, synthesis, and biological evaluation of 2-arylethenylquinoline derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2015, 89, 349-361.
[] [PMID: 25462251]
Zhang, C.; Du, Q.Y.; Chen, L.D.; Wu, W.H.; Liao, S.Y.; Yu, L.H.; Liang, X.T. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer’s disease. Eur. J. Med. Chem., 2016, 116, 200-209.
[] [PMID: 27061983]
Sun, Q.; Peng, D.Y.; Yang, S.G.; Zhu, X.L.; Yang, W.C.; Yang, G.F. Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase. Bioorg. Med. Chem., 2014, 22(17), 4784-4791.
[] [PMID: 25088549]
Zha, X.; Lamba, D.; Zhang, L.; Lou, Y.; Xu, C.; Kang, D.; Chen, L.; Xu, Y.; Zhang, L.; De Simone, A.; Samez, S.; Pesaresi, A.; Stojan, J.; Lopez, M.G.; Egea, J.; Andrisano, V.; Bartolini, M. Novel Tacrine-Benzofuran hybrids as potent multitarget-directed ligands for the treatment of Alzheimer’s disease: Design, synthesis, biological evaluation, and X-ray crystallography. J. Med. Chem., 2016, 59(1), 114-131.
[] [PMID: 26632651]
Shidore, M.; Machhi, J.; Shingala, K.; Murumkar, P.; Sharma, M.K.; Agrawal, N.; Tripathi, A.; Parikh, Z.; Pillai, P.; Yadav, M.R. Benzylpiperidine-linked diarylthiazoles as potential anti-Alzheimer’s agents: Synthesis and biological evaluation. J. Med. Chem., 2016, 59(12), 5823-5846.
[] [PMID: 27253679]
Li, Q.; He, S.; Chen, Y.; Feng, F.; Qu, W.; Sun, H. Donepezil-based multi-functional cholinesterase inhibitors for treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2018, 158, 463-477.
[] [PMID: 30243151]
Meena, P.; Nemaysh, V.; Khatri, M.; Manral, A.; Luthra, P.M.; Tiwari, M. Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer’s disease. Bioorg. Med. Chem., 2015, 23(5), 1135-1148.
[] [PMID: 25624107]
Yerdelen, K.O.; Koca, M.; Anil, B.; Sevindik, H.; Kasap, Z.; Halici, Z.; Turkaydin, K.; Gunesacar, G. Synthesis of donepezil-based multifunctional agents for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2015, 25(23), 5576-5582.
[] [PMID: 26514744]
Mishra, C.B.; Kumari, S.; Manral, A.; Prakash, A.; Saini, V.; Lynn, A.M.; Tiwari, M. Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2017, 125, 736-750.
[] [PMID: 27721157]
Huang, L.; Miao, H.; Sun, Y.; Meng, F.; Li, X. Discovery of indanone derivatives as multi-target-directed ligands against Alzheimer’s disease. Eur. J. Med. Chem., 2014, 87, 429-439.
[] [PMID: 25282266]
Liu, Q.; Qiang, X.; Li, Y.; Sang, Z.; Li, Y.; Tan, Z.; Deng, Y. Design, synthesis and evaluation of chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg. Med. Chem., 2015, 23(5), 911-923.
[] [PMID: 25678013]
Tonelli, M.; Catto, M.; Tasso, B.; Novelli, F.; Canu, C.; Iusco, G.; Pisani, L.; Stradis, A.D.; Denora, N.; Sparatore, A.; Boido, V.; Carotti, A.; Sparatore, F. Multitarget therapeutic leads for Alzheimer’s disease: Quinolizidinyl derivatives of bi- and tricyclic systems as dual inhibitors of cholinesterases and -amyloid (A) aggregation. ChemMedChem, 2015, 10(6), 1040-1053.
[] [PMID: 25924599]
Jiang, N.; Li, S.Y.; Xie, S.S.; Li, Z.R.; Wang, K.D.G.; Wang, X.B.; Kong, L.Y. Design, synthesis and evaluation of multifunctional salphen derivatives for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2014, 87, 540-551.
[] [PMID: 25290683]
Jourdan, J.P.; Since, M.; El Kihel, L.; Lecoutey, C.; Corvaisier, S.; Legay, R.; Sopkova-de Oliveira Santos, J.; Cresteil, T.; Malzert-Fréon, A.; Rochais, C.; Dallemagne, P. Novel benzylidenephenylpyrrolizinones with pleiotropic activities potentially useful in Alzheimer’s disease treatment. Eur. J. Med. Chem., 2016, 114, 365-379.
[] [PMID: 27046230]
Wang, Z.; Hu, J.; Yang, X.; Feng, X.; Li, X.; Huang, L.; Chan, A.S.C. Design, synthesis, and evaluation of orally bioavailable quinoline-indole derivatives as innovative multitarget-directed ligands: Promotion of cell proliferation in the adult murine hippocampus for the treatment of Alzheimer’s disease. J. Med. Chem., 2018, 61(5), 1871-1894.
[] [PMID: 29420891]
Sharma, P.; Tripathi, A.; Tripathi, P.N.; Prajapati, S.K.; Seth, A.; Tripathi, M.K.; Srivastava, P.; Tiwari, V.; Krishnamurthy, S.; Shrivastava, S.K. Design and development of multitarget-directed N-Benzylpiperidine analogs as potential candidates for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2019, 167, 510-524.
[] [PMID: 30784883]
Zhu, Z.; Yang, T.; Zhang, L.; Liu, L.; Yin, E.; Zhang, C.; Guo, Z.; Xu, C.; Wang, X. Inhibiting Aβ toxicity in Alzheimer’s disease by a pyridine amine derivative. Eur. J. Med. Chem., 2019, 168, 330-339.
[] [PMID: 30826509]
Abe, I.; Morita, H. Structure and function of the chalcone synthase superfamily of plant type III polyketide synthases. Nat. Prod. Rep., 2010, 27(6), 809-838.
[] [PMID: 20358127]
Mahapatra, D.K.; Asati, V.; Bharti, S.K. Chalcones and their therapeutic targets for the management of diabetes: Structural and pharmacological perspectives. Eur. J. Med. Chem., 2015, 92, 839-865.
[] [PMID: 25638569]
Sharma, V.; Kumar, V.; Kumar, P. Heterocyclic chalcone analogues as potential anticancer agents. Anti-Cancer Agent. Me, 2013, 13(3), 422-432.
Mahapatra, D.K.; Bharti, S.K. Therapeutic potential of chalcones as cardiovascular agents. Life Sci., 2016, 148, 154-172.
[] [PMID: 26876916]
Li, Y.S.; Matsunaga, K.; Kato, R.; Ohizumi, Y. Verbenachalcone, a novel dimeric dihydrochalcone with potentiating activity on nerve growth factor-action from Verbena littoralis. J. Nat. Prod., 2001, 64(6), 806-808.
[] [PMID: 11421751]
Sahu, N.K.; Balbhadra, S.S.; Choudhary, J.; Kohli, D.V. Exploring pharmacological significance of chalcone scaffold: A review. Curr. Med. Chem., 2012, 19(2), 209-225.
[] [PMID: 22320299]
Cai, Y.Z.; Mei., Sun Jie Xing; Luo, Q.; Corke, H. Structure-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants. Life Sci., 2006, 78(25), 2872-2888.
[] [PMID: 16325868]
Liu, H.R.; Zhou, C.; Fan, H.Q.; Tang, J.J.; Liu, L.B.; Gao, X.H.; Wang, Q.A.; Liu, W.K. Novel potent and selective acetylcholinesterase inhibitors as potential drugs for the treatment of Alzheimer’s disease: Synthesis, pharmacological evaluation, and molecular modeling of amino-alkyl-substituted fluoro-chalcones derivatives. Chem. Biol. Drug Des., 2015, 86(4), 517-522.
[] [PMID: 25588967]
Diaz-Rubio, L.; Hernandez-Martinez, R.; Estolano-Cobian, A.; Chavez-Velasco, D.; Salazar-Aranda, R.; de Torres, N.W.; Rivero, I.A.; Garcia-Gonzalez, V.; Ramos, M.A.; Cordova-Guerrero, I. Synthesis, Biological evaluation and docking studies of chalcone and flavone analogs as antioxidants and acetylcholinesterase inhibitors. Appl. Sci. (Basel), 2019, 9(3)
Ma, L.; Yang, Z.; Li, C.; Zhu, Z.; Shen, X.; Hu, L. Design, synthesis and SAR study of hydroxychalcone inhibitors of human β-secretase (BACE1). J. Enzyme Inhib. Med. Chem., 2011, 26(5), 643-648.
[] [PMID: 21222511]
Kang, J.E.; Cho, J.K.; Curtis-Long, M.J.; Ryu, H.W.; Kim, J.H.; Kim, H.J.; Yuk, H.J.; Kim, D.W.; Park, K.H. Inhibitory evaluation of sulfonamide chalcones on β-secretase and acylcholinesterase. Molecules, 2012, 18(1), 140-153.
[] [PMID: 23344193]
Cong, L.; Dong, X.; Wang, Y.; Deng, Y.; Li, B.; Dai, R. On the role of synthesized hydroxylated chalcones as dual functional amyloid-β aggregation and ferroptosis inhibitors for potential treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2019, 166, 11-21.
[] [PMID: 30684867]
Mechoulam, R.; Peters, M.; Murillo-Rodriguez, E.; Hanuš, L.O. Cannabidio––recent advances. Chem. Biodivers., 2007, 4(8), 1678-1692.
[] [PMID: 17712814]
ElSohly, M.A.; Radwan, M.M.; Gul, W.; Chandra, S.; Galal, A. Phytochemistry of cannabis sativa L. in phytocannabinoids: unraveling the complex chemistry and pharmacology of cannabis sativa; Kinghorn, A. D.; Falk, H.; Gibbons, S.; Kobayashi, J., Eds. In: Springer International Publishing Ag: Cham,; , 2017; 103, pp. 1-36.
Pertwee, R.G. Cannabinoid pharmacology: The first 66 years. Br. J. Pharmacol., 2006, 147(Suppl. 1), S163-S171.
[] [PMID: 16402100]
Li, H.; Liu, Y.; Tian, D.; Tian, L.; Ju, X.; Qi, L.; Wang, Y.; Liang, C. Overview of cannabidiol (CBD) and its analogues: Structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer’s disease. Eur. J. Med. Chem., 2020.192112163
[] [PMID: 32109623]
Libro, R.; Diomede, F.; Scionti, D.; Piattelli, A.; Grassi, G.; Pollastro, F.; Bramanti, P.; Mazzon, E.; Trubiani, O. Cannabidiol modulates the expression of Alzheimer’s disease-related genes in mesenchymal stem cells. Int. J. Mol. Sci., 2016, 18(1)E26
[] [PMID: 28025562]
Iuvone, T.; Esposito, G.; Esposito, R.; Santamaria, R.; Di Rosa, M.; Izzo, A.A. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J. Neurochem., 2004, 89(1), 134-141.
[] [PMID: 15030397]
Esposito, G.; Scuderi, C.; Valenza, M.; Togna, G.I.; Latina, V.; De Filippis, D.; Cipriano, M.; Carratù, M.R.; Iuvone, T.; Steardo, L. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One, 2011, 6(12)e28668
[] [PMID: 22163051]
Gallelli, C.A.; Calcagnini, S.; Romano, A.; Koczwara, J.B.; de Ceglia, M.; Dante, D.; Villani, R.; Giudetti, A.M.; Cassano, T.; Gaetani, S. Modulation of the oxidative stress and lipid peroxidation by endocannabinoids and their lipid analogues. Antioxidants, 2018, 7(7)E93
[] [PMID: 30021985]
Hung, C.L.; Chen, C.C. Computational approaches for drug discovery. Drug Dev. Res., 2014, 75(6), 412-418.
[] [PMID: 25195585]
Leelananda, S.P.; Lindert, S. Computational methods in drug discovery. Beilstein J. Org. Chem., 2016, 12, 2694-2718.
[] [PMID: 28144341]
Dighe, S.N.; Deora, G.S.; De la Mora, E.; Nachon, F.; Chan, S.; Parat, M-O.; Brazzolotto, X.; Ross, B.P. Discovery and structure–activity relationships of a highly selective butyrylcholinesterase inhibitor by structure-based virtual screening. J. Med. Chem., 2016, 59(16), 7683-7689.
[] [PMID: 27405689]
Chu, M.; Chen, X.; Wang, J.; Guo, L.; Wang, Q.; Gao, Z.; Kang, J.; Zhang, M.; Feng, J.; Guo, Q.; Li, B.; Zhang, C.; Guo, X.; Chu, Z.; Wang, Y. Polypharmacology of berberine based on multi-target binding motifs. Front. Pharmacol., 2018, 9, 801.
[] [PMID: 30087614]
Morgan, S.; Grootendorst, P.; Lexchin, J.; Cunningham, C.; Greyson, D. The cost of drug development: A systematic review. Health Policy, 2011, 100(1), 4-17.
[] [PMID: 21256615]
Wang, Z.M.; Cai, P.; Liu, Q.H.; Xu, D.Q.; Yang, X.L.; Wu, J.J.; Kong, L.Y.; Wang, X.B. Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2016, 123, 282-297.
[] [PMID: 27484514]
Jia, L.; Zhu, M.; Kong, C.; Pang, Y.; Zhang, H.; Qiu, Q.; Wei, C.; Tang, Y.; Wang, Q.; Li, Y.; Li, T.; Li, F.; Wang, Q.; Li, Y.; Wei, Y.; Jia, J. Blood neuro-exosomal synaptic proteins predict Alzheimer’s disease at the asymptomatic stage. Alzheimers Dement., 2020.
[] [PMID: 32776690]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy