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Recent Progress in the Treatment Strategies for Alzheimer’s Disease

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Computational Modeling of Drugs Against Alzheimer’s Disease

Part of the book series: Neuromethods ((NM,volume 203))

Abstract

Alzheimer’s disease (AD) is a neurological ailment that affects older people and causes a steady decline in their cognitive function. The cognitive impairments found are presumed to be the result of synapse disruption and neurochemical deficits. Several neurochemical abnormalities have been found throughout progressive aging, and these have been connected to cognitive dysfunction seen in the sporadic stage of AD. There are various hypotheses explaining AD, such as aberrant deposits of amyloid β (Aβ) protein in the extracellular spaces of neurons, production of twisted fibers of tau proteins inside neurons, cholinergic neuron damage, inflammation, oxidative stress, and so on, and many anti-AD therapeutics have been developed based on these hypotheses. While current pharmacological treatments assist in relieving the symptoms of AD and enhance a patient’s quality of life, they do not halt or cure the disease. Presently, targeted drug delivery to the central nervous system (CNS) for AD therapy is hampered by the difficulties posed by blood-brain interfaces surrounding the CNS, reducing therapeutic bioavailability. Among innovative ways to overcome these restrictions and successfully deliver pharmaceuticals to the CNS, nanoparticles (NPs) can overcome these barriers, offering new therapeutic strategies in terms of dealing drugs to cross the blood-brain barrier (BBB) and enter the brain more adequately. Various innovative therapeutic options for the treatment of AD have shown promising results in preclinical research and are currently being tested in clinical trials throughout the last decade. In addition to generating chemical entities, various natural compounds such as alkaloids, terpenoids, flavonoids, and curcumin have been isolated and evaluated for AD, and all demonstrated promising actions against a range of targets. Moreover, computational techniques have also proven to be quite useful in reducing time and money when developing new therapies. Molecular modeling, virtual screening, and docking have been widely used by researchers worldwide in recent years. These techniques have already aided in the development of several promising compounds. The purpose of this chapter is to summarize and highlight recent advancements in research on the development of novel therapies and their implications in the treatment of AD.

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References

  1. Samanta S, Ramesh M, Govindaraju T (2022) Chapter 1: Alzheimer’s is a multifactorial disease. In: Alzheimer’s disease: recent findings in pathophysiology. Diagnostic and therapeutic modalities, pp 1–34. https://doi.org/10.1039/9781839162732-00001

    Chapter  Google Scholar 

  2. Alzheimer’s Association (2021) Alzheimer’s disease facts and figures. Alzheimers Dement 17(3):327–406

    Google Scholar 

  3. Onyang IG, Jauregui GV, Čarná M, Bennett JP, Stokin GB (2021) Neuroinflammation in Alzheimer’s disease. Biomedicine 9(5):524. https://doi.org/10.3390/biomedicines9050524

    Article  CAS  Google Scholar 

  4. Tatulian SA (2022) Challenges and hopes for Alzheimer’s disease. Drug Discov Today. https://doi.org/10.1016/j.drudis.2022.01.016

  5. Gauthier S, Rosa-Neto P, Morais JA, Webster C (2021) World Alzheimer report 2021: journey through the diagnosis of dementia. Alzheimer’s Disease International, London

    Google Scholar 

  6. Srivastava S, Ahmad R, Khare SK (2021) Alzheimer’s disease and its treatment by different approaches: a review. Eur J Med Chem 216:113320. https://doi.org/10.1016/j.ejmech.2021.113320

    Article  CAS  PubMed  Google Scholar 

  7. Kumar V, Ojha PK, Saha A, Roy K (2020) Exploring 2D-QSAR for prediction of beta-secretase 1 (BACE1) inhibitory activity against Alzheimer’s disease. SAR QSAR Environ Res 31(2):87–133. https://doi.org/10.1080/1062936X.2019.1695226

    Article  CAS  PubMed  Google Scholar 

  8. Rajasekhar K, Govindaraju T (2018) Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer’s disease. RSC Adv 8(42):23780–23804. https://doi.org/10.1039/C8RA03620A

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lei G, Zhong MB, Larry Z, Bin Z, Dongming C (2022) Sex differences in Alzheimer’s disease: insights from the multiomics landscape. Biol Psychiatry 91(1):61–71. https://doi.org/10.1016/j.biopsych.2021.02.968

    Article  CAS  Google Scholar 

  10. Konstantina GY, Papageorgiou SG (2020) Current and future treatments in Alzheimer disease: an update. J Cent Nerv Syst 12:1–12. https://doi.org/10.1177/1179573520907397

    Article  Google Scholar 

  11. Kejing L, Ji N, Zhang X, Qiao W, Tang Z, Gou X (2019) Drug development for Alzheimer’s disease. J Drug Target 27(2):164–173. https://doi.org/10.1080/1061186X.2018.1474361

    Article  Google Scholar 

  12. Roy K (ed) (2018) Computational modeling of drugs against Alzheimer’s disease. Springer New York, Springer Science + Business Media, LLC, part of Springer Nature 2018. https://doi.org/10.1007/978-1-4939-7404-7

  13. Zhang B, Zhao J, Wang Z, Guo P, Liu A, Du G (2021) Identification of multi-target anti-AD chemical constituents from traditional Chinese medicine formulae by integrating virtual screening and in vitro validation. Front Pharmacol 12:709607. https://doi.org/10.3389/fphar.2021.709607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nadeem MS, Khan JA, Rashid U (2021) Fluoxetine and sertraline based multitarget inhibitors of cholinesterases and monoamine oxidase-A/B for the treatment of Alzheimer’s disease: synthesis, pharmacology and molecular modeling studies. Int J Biol Macromol 193:19–26. https://doi.org/10.1016/j.ijbiomac.2021.10.102

    Article  CAS  PubMed  Google Scholar 

  15. Brunetti L, Leuci R, Carrieri A, Catto M, Occhineri S, Vinci G, Piemontese L (2022) Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer’s disease. Eur J Med Chem 237:114358. https://doi.org/10.1016/j.ejmech.2022.114358

    Article  CAS  PubMed  Google Scholar 

  16. Ajala A, Uzairu A, Shallangwa GA, Abechi SE (2022) 2D QSAR, design, docking study and ADMET of some N-aryl derivatives concerning inhibitory activity against Alzheimer disease. Future J Pharm Sci 8(1):1–14. https://doi.org/10.1186/s43094-022-00420-w

    Article  Google Scholar 

  17. Ambure P, Bhat J, Puzyn T, Roy K (2019) Identifying natural compounds as multi-target-directed ligands against Alzheimer’s disease: an in silico approach. J Biomol Struct Dyn 37(5):1282–1306. https://doi.org/10.1080/07391102.2018.1456975

    Article  CAS  PubMed  Google Scholar 

  18. Kumar V, Saha A, Roy K (2020) In silico modeling for dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes in Alzheimer’s disease. Comput Biol Chem 88:107355. https://doi.org/10.1016/j.compbiolchem.2020.107355

    Article  CAS  PubMed  Google Scholar 

  19. Kumar A, Nisha CM, Silakari C, Sharma I, Anusha K, Gupta N, Kumar A (2016) Current and novel therapeutic molecules and targets in Alzheimer’s disease. J Formos Med Assoc 115(1):3–10. https://doi.org/10.1016/j.jfma.2015.04.001

    Article  CAS  PubMed  Google Scholar 

  20. Karran E, De Strooper B (2022) The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov 21(4):306–318

    Article  CAS  PubMed  Google Scholar 

  21. Ma C, Hong F, Yang S (2022) Amyloidosis in Alzheimer’s disease: pathogeny, etiology, and related therapeutic directions. Molecules 27(4):1210. https://doi.org/10.3390/molecules27041210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cho Y, Bae HG, Okun E, Arumugam TV, Jo DG (2022) Physiology and pharmacology of amyloid precursor protein. Pharmacol Ther:108122. https://doi.org/10.1016/j.pharmthera.2022.108122

  23. Mashal Y, Abdelhady H, Iyer AK (2022) Comparison of tau and amyloid-β targeted immunotherapy nanoparticles for Alzheimer’s disease. Biomol Ther 12(7):1001. https://doi.org/10.3390/biom12071001

    Article  CAS  Google Scholar 

  24. Aillaud I, Funke SA (2023) Tau aggregation inhibiting peptides as potential therapeutics for Alzheimer disease. Cell Mol Neurobiol 43(3):951–961

    Article  CAS  PubMed  Google Scholar 

  25. González A, Singh SK, Churruca M, Maccioni RB (2022) Alzheimer’s disease and tau self-assembly: in the search of the missing link. Int J Mol Sci 23(8):4192. https://doi.org/10.3390/ijms23084192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kumar K, Kumar A, Keegan RM, Deshmukh R (2018) Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease. Biomed Pharmacother 98:297–307. https://doi.org/10.1016/j.biopha.2017.12.053

    Article  CAS  PubMed  Google Scholar 

  27. Bozzo F, Mirra A, Carrì MT (2017) Oxidative stress and mitochondrial damage in the pathogenesis of ALS: new perspectives. Neurosci Lett 636:3–8. https://doi.org/10.1016/j.neulet.2016.04.065

    Article  CAS  PubMed  Google Scholar 

  28. Bai R, Guo J, Ye XY, Xie Y, Xie T (2022) Oxidative stress: the core pathogenesis and mechanism of Alzheimer’s disease. Ageing Res Rev:101619. https://doi.org/10.1016/j.arr.2022.101619

  29. de Oliveira J, Kucharska E, Garcez ML, Rodrigues MS, Quevedo J, Moreno-Gonzalez I, Budni J (2021) Inflammatory cascade in Alzheimer’s disease pathogenesis: a review of experimental findings. Cell 10(10):2581. https://doi.org/10.3390/cells10102581

    Article  CAS  Google Scholar 

  30. Whitson HE, Colton C, El Khoury J, Gate D, Goate A, Heneka MT, Terrando N (2022) Infection and inflammation: new perspectives on Alzheimer’s disease. Brain Behav Immun Health:100462. https://doi.org/10.1016/j.bbih.2022.100462

  31. Zeng L, Wang M, Zhou J, Wang X, Zhang Y, Su P (2022) A hypothesis: retrotransposons as a relay of epigenetic marks in intergenerational epigenetic inheritance. Gene 817:146229. https://doi.org/10.1016/j.gene.2022.146229

    Article  CAS  PubMed  Google Scholar 

  32. Millan MJ (2022) The epigenetic dimension of Alzheimer’s disease: causal, consequence, or curiosity. Dialogues Clin Neurosci. https://doi.org/10.31887/DCNS.2014.16.3/mmillan

  33. Wang SC, Oelze B, Schumacher A (2008) Age-specific epigenetic drift in late-onset Alzheimer’s disease. PLoS One 3(7):e2698. https://doi.org/10.1371/journal.pone.0002698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bakulski KM, Dolinoy DC, Sartor MA, Paulson HL, Konen JR, Lieberman AP, Rozek LS (2012) Genome-wide DNA methylation differences between late-onset Alzheimer’s disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis 29(3):571–588. https://doi.org/10.3233/JAD-2012-111223

    Article  CAS  PubMed  Google Scholar 

  35. Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A, Pennisi G (2004) Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med 42(9):1032–1035. https://doi.org/10.1515/CCLM.2004.208

    Article  CAS  PubMed  Google Scholar 

  36. Ding H, Dolan PJ, Johnson GV (2008) Histone deacetylase 6 interacts with the microtubule-associated protein tau. J Neurochem 106(5):2119–2130. https://doi.org/10.1111/j.1471-4159.2008.05564.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tang YP, Gershon ES (2022) Genetic studies in Alzheimer’s disease. Dialogues Clin Neurosci. https://doi.org/10.31887/DCNS.2003.5.1/yptang

  38. Uddin MS, Hasana S, Hossain M, Islam M, Behl T, Perveen A, Ashraf GM (2021) Molecular genetics of early-and late-onset Alzheimer’s disease. Curr Gene Ther 21(1):43–52. https://doi.org/10.2174/1566523220666201123112822

    Article  CAS  PubMed  Google Scholar 

  39. Chen ZR, Huang JB, Yang SL, Hong FF (2022) Role of cholinergic signaling in Alzheimer’s disease. Molecules 27(6):1816. https://doi.org/10.3390/molecules27061816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McNerney M, Heath A, Narayanan S, Yesavage J (2022) Repetitive transcranial magnetic stimulation improves brain-derived neurotrophic factor and cholinergic signaling in the 3xTgAD mouse model of Alzheimer’s disease. J Alzheimers Dis (Preprint):1–9. https://doi.org/10.3233/JAD-215361

  41. Giacobini E, Cuello AC, Fisher A (2022) Reimagining cholinergic therapy for Alzheimer’s disease. Brain. https://doi.org/10.1093/brain/awac096

  42. Kumar V, De P, Ojha PK, Saha A, Roy K (2020) A multi-layered variable selection strategy for QSAR modeling of butyrylcholinesterase inhibitors. Curr Top Med Chem 20(18):1601–1627. https://doi.org/10.2174/1568026620666200616142753

    Article  CAS  PubMed  Google Scholar 

  43. Kumar V, Saha A (2020) Chemometric modeling of structurally diverse carbamates for the inhibition of acetylcholinesterase (AChE) enzyme in Alzheimer’s disease. Int J Quant Struct Prop Relatsh 5(3):6–60. https://doi.org/10.4018/IJQSPR.2020070102

    Article  CAS  Google Scholar 

  44. Aaldijk E, Vermeiren Y (2022) The role of serotonin within the microbiota-gut-brain axis in the development of Alzheimer’s disease: a narrative review. Ageing Res Rev:101556. https://doi.org/10.1016/j.arr.2021.101556

  45. Nykamp MJ, Zorumski CF, Reiersen AM, Nicol GE, Cirrito J, Lenze EJ (2022) Opportunities for drug repurposing of serotonin reuptake inhibitors: potential uses in inflammation, infection, cancer, neuroprotection, and Alzheimer’s disease prevention. Pharmacopsychiatry 55(01):24–29. https://doi.org/10.1055/a-1686-9620

    Article  CAS  PubMed  Google Scholar 

  46. Abd-Elrahman KS, Ferguson SS (2022) Noncanonical metabotropic glutamate receptor 5 signaling in Alzheimer’s disease. Annu Rev Pharmacol Toxicol 62:235–254. https://doi.org/10.1146/annurev-pharmtox-021821-091747

    Article  CAS  PubMed  Google Scholar 

  47. Sulkowski G, Wencel PL, Dąbrowska-Bouta B, Struzynska L, Strosznajder R (2022) Alterations in the transcriptional profile of genes related to glutamatergic signalling in animal models of Alzheimer’s disease. The effect of fingolimod. Folia Neuropathol 60(1):10–23. https://doi.org/10.5114/fn.2022.114302

    Article  PubMed  Google Scholar 

  48. Pinky PD, Pfitzer JC, Senfeld J, Hong H, Bhattacharya S, Suppiramaniam V, Reed MN (2022) Recent insights on glutamatergic dysfunction in Alzheimer’s disease and therapeutic implications. Neuroscientist:10738584211069897. https://doi.org/10.1177/10738584211069897

  49. Huang Q, Zhang C, Qu S, Dong S, Ma Q, Hao Y, Shi Y (2022) Chinese herbal extracts exert neuroprotective effect in Alzheimer’s disease mouse through the dopaminergic synapse/apoptosis signaling pathway. Front Pharmacol 13. https://doi.org/10.3389/fphar.2022.817213

  50. Gloria Y, Ceyzériat K, Tsartsalis S, Millet P, Tournier BB (2021) Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer’s disease. Sci Rep 11(1):1–11

    Article  Google Scholar 

  51. Kemppainen N, Laine M, Laakso MP, Kaasinen V, Någren K, Vahlberg T, Rinne JO (2003) Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer’s disease. Eur J Neurosci 18(1):149–154. https://doi.org/10.1046/j.1460-9568.2003.02716.x

    Article  CAS  PubMed  Google Scholar 

  52. Yu ZY, Yi X, Wang YR, Zeng GH, Tan CR, Cheng Y, Liu YH (2022) Inhibiting α1-adrenergic receptor signaling pathway ameliorates AD-type pathologies and behavioral deficits in APPswe/PS1 mouse model. J Neurochem 161(3):293–307. https://doi.org/10.1111/jnc.15603

    Article  CAS  PubMed  Google Scholar 

  53. Bekdash RA (2021) The cholinergic system, the adrenergic system and the neuropathology of Alzheimer’s disease. Int J Mol Sci 22(3):1273. https://doi.org/10.3390/ijms22031273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Goodman AM, Langner BM, Jackson N, Alex C, McMahon LL (2021) Heightened hippocampal β-adrenergic receptor function drives synaptic potentiation and supports learning and memory in the TgF344-AD rat model during prodromal Alzheimer’s disease. J Neurosci 41(26):5747–5761. https://doi.org/10.1523/JNEUROSCI.0119-21.2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li X, Li J, Huang Y, Gong Q, Fu Y, Xu Y, Li J (2022) The novel therapeutic strategy of vilazodone-donepezil chimeras as potent triple-target ligands for the potential treatment of Alzheimer’s disease with comorbid depression. Eur J Med Chem 229:114045. https://doi.org/10.1016/j.ejmech.2021.114045

    Article  CAS  PubMed  Google Scholar 

  56. Vaz M, Silva V, Monteiro C, Silvestre S (2022) Role of aducanumab in the treatment of Alzheimer’s disease: challenges and opportunities. Clin Interv Aging 17:797. https://doi.org/10.2147/CIA.S325026

    Article  PubMed  PubMed Central  Google Scholar 

  57. Pritam P, Deka R, Bhardwaj A, Srivastava R, Kumar D, Jha AK, Jha SK (2022) Antioxidants in Alzheimer’s disease: current therapeutic significance and future prospects. Biology 11(2):212. https://doi.org/10.3390/biology11020212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kabir MT, Rahman MH, Shah M, Jamiruddin MR, Basak D, Al-Harrasi A, Abdel-Daim MM (2022) Therapeutic promise of carotenoids as antioxidants and anti-inflammatory agents in neurodegenerative disorders. Biomed Pharmacother 146:112610. https://doi.org/10.1016/j.biopha.2021.112610

    Article  CAS  PubMed  Google Scholar 

  59. Brod SA (2022) Anti-inflammatory agents: an approach to prevent cognitive decline in Alzheimer’s disease. J Alzheimers Dis 85(2):457–472. https://doi.org/10.3233/JAD-215125

    Article  CAS  PubMed  Google Scholar 

  60. Galimi R (2022) Interaction between anti-Alzheimer’s disease drugs and antipsychotic agents in the treatment of behavioral and psychological symptoms: extrapyramidal side effects. Adv Neurol Neurosci 5(2):108–119

    Google Scholar 

  61. Phelps EB, Swantek S (2022) Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. In: Essential reviews in geriatric psychiatry. Springer, Cham, pp 313–317

    Chapter  Google Scholar 

  62. Mokhtari T (2022) Targeting autophagy and neuroinflammation pathways with plant-derived natural compounds as potential antidepressant agents. Phytother Res. https://doi.org/10.1002/ptr.7551

  63. He Y, Li H, Huang J, Huang S, Bai Y, Li Y, Huang W (2021) Efficacy of antidepressant drugs in the treatment of depression in Alzheimer disease patients: a systematic review and network meta-analysis. J Psychopharmacol 35(8):901–909. https://doi.org/10.1177/02698811211030181

    Article  CAS  PubMed  Google Scholar 

  64. Correia AS, Vale N (2021) Antidepressants in Alzheimer’s disease: a focus on the role of mirtazapine. Pharmaceuticals 14(9):930. https://doi.org/10.3390/ph14090930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rosoff DB, Bell AS, Jung J, Wagner J, Mavromatis LA, Lohoff FW (2022) Mendelian randomization study of PCSK9 and HMG-CoA reductase inhibition and cognitive function. J Am Coll Cardiol 80(7):653–662

    Article  CAS  PubMed  Google Scholar 

  66. Cheraghzadeh M, Nazeri Z, Mohammadi A, Azizidoost S, Aberomand M, Kheirollah A (2021) Amyloid Beta sharply increases HMG-CoA reductase protein levels in astrocytes isolated from C57BL/6 mice. Gene Rep 23:101070. https://doi.org/10.1016/j.genrep.2021.101070

    Article  CAS  Google Scholar 

  67. Cardinali CA, Martins YA, Torrão AS (2021) Use of hormone therapy in postmenopausal women with Alzheimer’s disease: a systematic review. Drugs Aging 38(9):769–791

    Article  PubMed  Google Scholar 

  68. Mitra S, Muni M, Shawon NJ, Das R, Emran TB, Sharma R, Sweilam SH (2022) Tacrine derivatives in neurological disorders: focus on molecular mechanisms and neurotherapeutic potential. Oxid Med Cell Longev. https://doi.org/10.1155/2022/7252882

  69. Makhaeva GF, Kovaleva NV, Boltneva NP, Rudakova EV, Lushchekina SV, Astakhova TY, Richardson RJ (2022) Bis-amiridines as acetylcholinesterase and butyrylcholinesterase inhibitors: N-functionalization determines the multitarget anti-Alzheimer’s activity profile. Molecules 27(3):1060. https://doi.org/10.3390/molecules27031060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yiannopoulou KG, Anastasiou AI, Zachariou V, Pelidou SH (2019) Reasons for failed trials of disease-modifying treatments for Alzheimer disease and their contribution in recent research. Biomedicine 7(4):97. https://doi.org/10.3390/biomedicines7040097

    Article  CAS  Google Scholar 

  71. Esang M, Gupta M (2021) Aducanumab as a novel treatment for Alzheimer’s disease: a decade of hope, controversies, and the future. Cureus 13(8). https://doi.org/10.7759/cureus.17591

  72. Pange SS, Patwekar M, Patwekar F, Alghamdi S, Babalghith AO, Abdulaziz O, Mallick J (2022) A potential notion on Alzheimer’s disease: nanotechnology as an alternative solution. J Nanomater. https://doi.org/10.1155/2022/6910811

  73. Nguyen TT, Nguyen TTD, Nguyen TKO, Vo TK (2021) Advances in developing therapeutic strategies for Alzheimer’s disease. Biomed Pharmacother 139:111623. https://doi.org/10.1016/j.biopha.2021.111623

    Article  CAS  PubMed  Google Scholar 

  74. Zeng H, Qi Y, Zhang Z, Liu C, Peng W, Zhang Y (2021) Nanomaterials toward the treatment of Alzheimer’s disease: recent advances and future trends. Chin Chem Lett 32(6):1857–1868. https://doi.org/10.1016/j.cclet.2021.01.014

    Article  CAS  Google Scholar 

  75. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29(4):341–345

    Article  CAS  PubMed  Google Scholar 

  76. Cano A, Turowski P, Ettcheto M, Duskey JT, Tosi G, Sánchez-López E, Boada M (2021) Nanomedicine-based technologies and novel biomarkers for the diagnosis and treatment of Alzheimer’s disease: from current to future challenges. J Nanobiotechnology 19(1):1–30

    Article  CAS  Google Scholar 

  77. Noori T, Dehpour AR, Sureda A, Sobarzo-Sanchez E, Shirooie S (2021) Role of natural products for the treatment of Alzheimer’s disease. Eur J Pharmacol 898:173974. https://doi.org/10.1016/j.ejphar.2021.173974

    Article  CAS  PubMed  Google Scholar 

  78. Mani R, Sha Sulthana A, Muthusamy G, Elangovan N (2022) Progress in the development of naturally derived active metabolites-based drugs: potential therapeutics for Alzheimer’s disease. Biotechnol Appl Biochem. https://doi.org/10.1002/bab.2317

  79. Zhang P, Xu S, Zhu Z, Xu J (2019) Multi-target design strategies for the improved treatment of Alzheimer’s disease. Eur J Med Chem 176:228–247. https://doi.org/10.1016/j.ejmech.2019.05.020

    Article  CAS  PubMed  Google Scholar 

  80. Benek O, Korabecny J, Soukup O (2020) A perspective on multi-target drugs for Alzheimer’s disease. Trends Pharmacol Sci 41(7):434–445. https://doi.org/10.1016/j.tips.2020.04.008

    Article  CAS  PubMed  Google Scholar 

  81. Zhu Y, Xiao K, Ma L, Xiong B, Fu Y, Yu H, Shen J (2009) Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and β-secretase. Bioorg Med Chem 17(4):1600–1613. https://doi.org/10.1016/j.bmc.2008.12.067

    Article  CAS  PubMed  Google Scholar 

  82. Fernández-Bachiller MI, Pérez C, Monjas L, Rademann J, Rodríguez-Franco MI (2012) New Tacrine–4-Oxo-4 H-chromene hybrids as multifunctional agents for the treatment of Alzheimer’s disease, with cholinergic, antioxidant, and β-amyloid-reducing properties. J Med Chem 55(3):1303–1317. https://doi.org/10.1021/jm201460y

    Article  CAS  PubMed  Google Scholar 

  83. Mohamed T, Yeung JC, Vasefi MS, Beazely MA, Rao PP (2012) Development and evaluation of multifunctional agents for potential treatment of Alzheimer’s disease: application to a pyrimidine-2, 4-diamine template. Bioorg Med Chem Lett 22(14):4707–4712. https://doi.org/10.1016/j.bmcl.2012.05.077

    Article  CAS  PubMed  Google Scholar 

  84. Viayna E, Sola I, Bartolini M, De Simone A, Tapia-Rojas C, Serrano FG, Muñoz-Torrero D (2014) Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents. J Med Chem 57(6):2549–2567. https://doi.org/10.1021/jm401824w

    Article  CAS  PubMed  Google Scholar 

  85. Domínguez JL, Fernández-Nieto F, Castro M, Catto M, Paleo MR, Porto S, Sussman F (2015) Computer-aided structure-based design of multitarget leads for Alzheimer’s disease. J Chem Inf Model 55(1):135–148. https://doi.org/10.1021/ci500555g

    Article  CAS  PubMed  Google Scholar 

  86. Hui AL, Chen Y, Zhu SJ, Gan CS, Pan J, Zhou A (2014) Design and synthesis of tacrine-phenothiazine hybrids as multitarget drugs for Alzheimer’s disease. Med Chem Res 23(7):3546–3557

    Article  CAS  Google Scholar 

  87. Jiang XY, Chen TK, Zhou JT, He SY, Yang HY, Chen Y, Sun HP (2018) Dual GSK-3β/AChE inhibitors as a new strategy for multitargeting anti-Alzheimer’s disease drug discovery. ACS Med Chem Lett 9(3):171–176. https://doi.org/10.1021/acsmedchemlett.7b00463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bolea I, Juarez-Jimenez J, de los Rı́os C, Chioua M, Pouplana R, Luque FJ, Samadi A (2011) Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1 H-indol-2-yl) methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease. J Med Chem 54(24):8251–8270. https://doi.org/10.1021/jm200853t

    Article  CAS  PubMed  Google Scholar 

  89. Wang L, Esteban G, Ojima M, Bautista-Aguilera OM, Inokuchi T, Moraleda I, Unzeta M et al (2014) Donepezil+ propargylamine+ 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer’s disease. Eur J Med Chem 80:543–561. https://doi.org/10.1016/j.ejmech.2014.04.078

    Article  CAS  PubMed  Google Scholar 

  90. Wu MY, Esteban G, Brogi S, Shionoya M, Wang L, Campiani G, Marco-Contelles J (2016) Donepezil-like multifunctional agents: design, synthesis, molecular modeling and biological evaluation. Eur J Med Chem 121:864–879. https://doi.org/10.1016/j.ejmech.2015.10.001

    Article  CAS  PubMed  Google Scholar 

  91. Sang Z, Pan W, Wang K, Ma Q, Yu L, Liu W (2017) Design, synthesis and biological evaluation of 3, 4-dihydro-2 (1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease. Bioorg Med Chem 25(12):3006–3017. https://doi.org/10.1016/j.bmc.2017.03.070

    Article  CAS  PubMed  Google Scholar 

  92. Lu C, Zhou Q, Yan J, Du Z, Huang L, Li X (2013) A novel series of tacrine–selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer’s disease. Eur J Med Chem 62:745–753. https://doi.org/10.1016/j.ejmech.2013.01.039

    Article  CAS  PubMed  Google Scholar 

  93. Xu Y, Zhang J, Wang H, Mao F, Bao K, Liu W, Li J (2018) Rational design of novel selective dual-target inhibitors of acetylcholinesterase and monoamine oxidase B as potential anti-Alzheimer’s disease agents. ACS Chem Neurosci 10(1):482–496. https://doi.org/10.1021/acschemneuro.8b00357

    Article  CAS  PubMed  Google Scholar 

  94. Xu YX, Wang H, Li XK, Dong SN, Liu WW, Gong Q, Mao F (2018) Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 143:33–47. https://doi.org/10.1016/j.ejmech.2017.08.025

    Article  CAS  PubMed  Google Scholar 

  95. Fernández-Bachiller MI, Pérez C, González-Munoz GC, Conde S, López MG, Villarroya M, Rodríguez-Franco MI (2010) Novel tacrine− 8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer’s disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J Med Chem 53(13):4927–4937. https://doi.org/10.1021/jm100329q

    Article  CAS  PubMed  Google Scholar 

  96. Li SY, Wang XB, Xie SS, Jiang N, Wang KD, Yao HQ, Kong LY (2013) Multifunctional tacrine–flavonoid hybrids with cholinergic, β-amyloid-reducing, and metal chelating properties for the treatment of Alzheimer’s disease. Eur J Med Chem 69:632–646. https://doi.org/10.1016/j.ejmech.2013.09.024

    Article  CAS  PubMed  Google Scholar 

  97. Xie SS, Wang XB, Li JY, Yang L, Kong LY (2013) Design, synthesis and evaluation of novel tacrine–coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease. Eur J Med Chem 64:540–553. https://doi.org/10.1016/j.ejmech.2013.03.051

    Article  CAS  PubMed  Google Scholar 

  98. Liu Q, Qiang X, Li Y, Sang Z, Li Y, Tan Z, Deng Y (2015) Design, synthesis and evaluation of chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 23(5):911–923. https://doi.org/10.1016/j.bmc.2015.01.042

    Article  CAS  PubMed  Google Scholar 

  99. Yan J, Hu J, Liu A, He L, Li X, Wei H (2017) Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer’s disease based on the fusion of donepezil and curcumin. Bioorg Med Chem 25(12):2946–2955. https://doi.org/10.1016/j.bmc.2017.02.048

    Article  CAS  PubMed  Google Scholar 

  100. Rosini M, Simoni E, Minarini A, Melchiorre C (2014) Multi-target design strategies in the context of Alzheimer’s disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces. Neurochem Res 39(10):1914–1923

    Article  CAS  PubMed  Google Scholar 

  101. Makhaeva GF, Lushchekina SV, Boltneva NP, Sokolov VB, Grigoriev VV, Serebryakova OG, Bachurin SO (2015) Conjugates of γ-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer disease. Sci Rep 5(1):1–11

    Article  Google Scholar 

  102. Rochais C, Lecoutey C, Gaven F, Giannoni P, Hamidouche K, Hedou D, Dallemagne P (2015) Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer’s disease: the design of donecopride. J Med Chem 58(7):3172–3187. https://doi.org/10.1021/acs.jmedchem.5b00115

    Article  CAS  PubMed  Google Scholar 

  103. Liu W, Wang H, Li X, Xu Y, Zhang J, Wang W, Li J (2018) Design, synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment. Bioorg Med Chem 26(12):3117–3125. https://doi.org/10.1016/j.bmc.2018.04.037

    Article  CAS  PubMed  Google Scholar 

  104. Huang W, Tang L, Shi Y, Huang S, Xu L, Sheng R, Hu Y (2011) Searching for the multi-target-directed ligands against Alzheimer’s disease: discovery of quinoxaline-based hybrid compounds with AChE, H3R and BACE 1 inhibitory activities. Bioorg Med Chem 19(23):7158–7167. https://doi.org/10.1016/j.bmc.2011.09.061

    Article  CAS  PubMed  Google Scholar 

  105. Mao F, Wang H, Ni W, Zheng X, Wang M, Bao K, Li J (2018) Design, synthesis, and biological evaluation of orally available first-generation dual-target selective inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) for the treatment of Alzheimer’s disease. ACS Chem Neurosci 9(2):328–345. https://doi.org/10.1021/acschemneuro.7b00345

    Article  CAS  PubMed  Google Scholar 

  106. Prati F, De Simone A, Bisignano P, Armirotti A, Summa M, Pizzirani D, Cavalli A (2015) Multitarget drug discovery for Alzheimer’s disease: triazinones as BACE-1 and GSK-3β inhibitors. Angew Chem 127(5):1598–1602. https://doi.org/10.1002/ange.201410456

    Article  Google Scholar 

  107. Di Martino RMC, De Simone A, Andrisano V, Bisignano P, Bisi A, Gobbi S, Belluti F (2016) Versatility of the curcumin scaffold: discovery of potent and balanced dual BACE-1 and GSK-3β inhibitors. J Med Chem 59(2):531–544. https://doi.org/10.1021/acs.jmedchem.5b00894

    Article  CAS  PubMed  Google Scholar 

  108. Xie S, Chen J, Li X, Su T, Wang Y, Wang Z, Li X (2015) Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer’s disease. Bioorg Med Chem 23(13):3722–3729. https://doi.org/10.1016/j.bmc.2015.04.009

    Article  CAS  PubMed  Google Scholar 

  109. Su T, Zhang T, Xie S, Yan J, Wu Y, Li X, Luo HB (2016) Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease. Sci Rep 6(1):1–14

    CAS  Google Scholar 

  110. Wang Z, Wang Y, Wang B, Li W, Huang L, Li X (2015) Design, synthesis, and evaluation of orally available clioquinol-moracin M hybrids as multitarget-directed ligands for cognitive improvement in a rat model of neurodegeneration in Alzheimer’s disease. J Med Chem 58(21):8616–8637. https://doi.org/10.1021/acs.jmedchem.5b01222

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

VK thanks the Indian Council of Medical Research (ICMR), New Delhi (File No: BMI/11(03)/2022, IRIS Cell No.: 2021-8243, dated: 13/05/2022) for financial support in the form of a Research Associateship (RA).

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  1. Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

    Vinay Kumar & Kunal Roy

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  1. Vinay Kumar
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    Kunal Roy

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Kumar, V., Roy, K. (2023). Recent Progress in the Treatment Strategies for Alzheimer’s Disease. In: Roy, K. (eds) Computational Modeling of Drugs Against Alzheimer’s Disease. Neuromethods, vol 203. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3311-3_1

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