Makbule Dilara ODABAŞI, Zekiye Tuba TÜYLÜ KÜÇÜKKILINÇ

Alzheimer Hastalığı Tedavisindeki Güncel Yaklaşımlar

Alzheimer hastalığı bilişsel ve hafıza bozukluğu ile karakterize ilerleyici ve geri dönüşü olmayan sinir hücrelerinin hasarına yol açan bir hastalıktır. Dünyanın önde gelen demans nedenidir ve Alzheimer hastalarının popülasyonu hızla artmaktadır. Hastalığın etiyolojisinin henüz tam olarak belirlenememesi, hasta popülasyonunun yıllar geçtikçe artması, radikal bir tedavinin olmayışı, hastaların yaşam kalitesini oldukça düşürmesi gibi sebepler hastalığın önemini arttırmakta ve araştırmacıları bu alana yönlendirmektedir. Bu derlemede Alzheimer ile ilgili genel bilgiler ve hastalığı modifiye edici, iyileştirici güncel tedavi yaklaşımları incelenmiştir.

Anahtar Kelimeler:

Alzheimer hastalığı, amiloid beta, tau proteini

Current Approaches in Alzheimer's Disease Treatment

Alzheimer's disease is a disease that causes progressive and irreversible damage to nerve cells, characterized by cognitive and memory impairment. It is the world's leading cause of dementia and the population of Alzheimer's patients is growing rapidly. The reasons such as the etiology of the disease not being determined yet, the increase in the patient population over the years, the lack of a radical treatment, the decrease in the quality of life of the patients increase the importance of the disease and direct the researchers to this field. In this review, general information about Alzheimer's and current treatment approaches that modify and improve the disease are examined.

Keywords:

Alzheimer's disease, amyloid beta, tau protein,

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1. Apostolova LG. Alzheimer Disease. Continuum (Minneap Minn). 2016;22(2):419-34.
2. Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer Disease. American Family Physician. 2011;83(12):1403-12.
3. Fish PV, Steadman D, Bayle ED, Whiting P. New approaches for the treatment of Alzheimer's disease. Bioorg Med Chem Lett. 2019;29(2):125-33.
4. Leinenga G, Koh WK, Götz J. A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease. 2021.
5. Du X, Wang X, Geng M. Alzheimer's disease hypothesis and related therapies. Transl Neurodegener. 2018;7:2.
6. Biran Y, Masters CL, Barnham KJ, Bush AI, Adlard PA. Pharmacotherapeutic targets in Alzheimer's disease. J Cell Mol Med. 2009;13(1):61-86.
7. Kuruva CS, Reddy PH. Amyloid beta modulators and neuroprotection in Alzheimer's disease: a critical appraisal. Drug Discov Today. 2017;22(2):223-33.
8. Panza F, Lozupone M, Solfrizzi V, Sardone R, Piccininni C, Dibello V, et al. BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Review of Neurotherapeutics. 2018;18(11):847-57.
9. Munro KM, Nash A, Pigoni M, Lichtenthaler SF, Gunnersen JM. Functions of the Alzheimer's Disease Protease BACE1 at the Synapse in the Central Nervous System. J Mol Neurosci. 2016;60(3):305-15.
10. Lao K, Ji N, Zhang X, Qiao W, Tang Z, Gou X. Drug development for Alzheimer's disease: review. J Drug Target. 2019;27(2):164-73.
11. Vaz M, Silvestre S. Alzheimer's disease: Recent treatment strategies. Eur J Pharmacol. 2020;887:173554.
12. Wolfe MS. gamma-Secretase inhibitors and modulators for Alzheimer's disease. J Neurochem. 2012;120 Suppl 1:89-98.
13. Tarassishin L, Y.I. Y, Bassit B, Li Y-M. Processing of Notch and amyloid precursor protein by γ-secretase is spatially distinct. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(49):17050-5.
14. Augelli-Szafran CE, We H-X, Zhang J, Lu D, Zhang J, Gu Y, et al. Discovery of Notch-Sparing γ-Secretase Inhibitors. Curr Alzheimer Res. 2010;7(3):207-9.
15. Iraji A, Khoshneviszadeh M, Firuzi O, Khoshneviszadeh M, Edraki N. Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands. Bioorg Chem. 2020;97:103649.
16. Sahlin C, Lord A, Magnusson K, Englund H, Almeida CG, Greengard P, et al. The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase. J Neurochem. 2007;101(3):854-62.
17. Postina R. Activation of alpha-secretase cleavage. J Neurochem. 2012;120 Suppl 1:46-54.
18. Lichtenthaler SF, Haass C. Amyloid at the cutting edge: activation of α-secretase prevents amyloidogenesis in an Alzheimer disease mouse model. Journal of Clinical Investigation. 2004;113(10):1384-7.
19. Mockett BG, Richter M, Abraham WC, Muller UC. Therapeutic Potential of Secreted Amyloid Precursor Protein APPsalpha. Front Mol Neurosci. 2017;10:30.
20. Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, et al. Structural Basis for Regulated Proteolysis by the alpha-Secretase ADAM10. Cell. 2017;171(7):1638-48 e7.
21. De Strooper B, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol. 2010;6(2):99-107.
22. Liao W, Jin G, Zhao M, Yang H. The effect of genistein on the content and activity of alpha- and beta-secretase and protein kinase C in Abeta-injured hippocampal neurons. Basic Clin Pharmacol Toxicol. 2013;112(3):182-5.
23. Khan TK, Wender PA, Alkon DL. Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents. J Cell Physiol. 2018;233(2):1523-34.
24. Lucke-Wold BP, Turner RC, Logsdon AF, Simpkins JW, Alkon DL, Smith KE, et al. Common mechanisms of Alzheimer's disease and ischemic stroke: the role of protein kinase C in the progression of age-related neurodegeneration. J Alzheimers Dis. 2015;43(3):711-24.
25. Imbimbo BP, Speroni F. β‐Amyloid Therapeutic Strategies for Alzheimer's Disease. Burger's Medicinal Chemistry and Drug Discovery2005.
26. Yang HQ, Pan J, Ba MW, Sun ZK, Ma GZ, Lu GQ, et al. New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing alpha-secretase activity. Eur J Neurosci. 2007;26(2):381-91.
27. Vellas B, Sol O, Snyder PJ, Ousset PJ, Haddad R, Maurin M, et al. EHT0202 in Alzheimers Disease: A 3-Month, Randomized, Placebo-Controlled, Double-Blind Study. Current Alzheimer Research. 2011;8(2):203-12.
28. Tang BL. Enhancing alpha-secretase Processing for Alzheimer's Disease-A View on SFRP1. Brain Sci. 2020;10(2).
29. Baptista FI, Henriques AG, Silva AM, Wiltfang J, da Cruz e Silva OA. Flavonoids as therapeutic compounds targeting key proteins involved in Alzheimer's disease. ACS Chem Neurosci. 2014;5(2):83-92.
30. Frisardi V, Solfrizzi V, Imbimbo BP, Capurso C, D'Introno A, Colacicco AM, et al. Towards Disease-Modifying Treatment of Alzheimers Disease: Drugs Targeting β-Amyloid. Current Alzheimer Research. 2010;7(1):40-55.
31. Dos Santos Guilherme M, Stoye NM, Rose-John S, Garbers C, Fellgiebel A, Endres K. The Synthetic Retinoid Acitretin Increases IL-6 in the Central Nervous System of Alzheimer Disease Model Mice and Human Patients. Front Aging Neurosci. 2019;11:182.
32. Araki W. Potential repurposing of oncology drugs for the treatment of Alzheimer's disease. BMC Medicine. 2013;11(82).
33. Pimenova AA, Thathiah A, De Strooper B, Tesseur I. Regulation of amyloid precursor protein processing by serotonin signaling. PLoS One. 2014;9(1):e87014.
34. Bradburn S, Murgatroyd C, Ray N. Neuroinflammation in mild cognitive impairment and Alzheimer's disease: A meta-analysis. Ageing Res Rev. 2019;50:1-8.
35. Imbimbo BP. The potential role of non-steroidal anti-inflammatory drugs in treating Alzheimer’s disease. Expert Opinion on Investigational Drugs. 2004;13(11):1469-81.
36. Nevado-Holgado AJ, Lovestone S. Determining the Molecular Pathways Underlying the Protective Effect of Non-Steroidal Anti-Inflammatory Drugs for Alzheimer's Disease: A Bioinformatics Approach. Comput Struct Biotechnol J. 2017;15:1-7.
37. Krishnendu PR, Arjun B, Vibina K, Nivea Cleo TS, Drisya NK, Mohandas R, et al. Review on Evaluating the Role of Nsaids for the Treatment of Alzheimer's Disease. International Journal of Applied Pharmaceutics. 2021:91-4.
38. Husna Ibrahim N, Yahaya MF, Mohamed W, Teoh SL, Hui CK, Kumar J. Pharmacotherapy of Alzheimer's Disease: Seeking Clarity in a Time of Uncertainty. Front Pharmacol. 2020;11:261.
39. Lichtenstein MP, Carriba P, Masgrau R, Pujol A, Galea E. Staging anti-inflammatory therapy in Alzheimer's disease. Front Aging Neurosci. 2010;2:142.
40. Ali MM, Ghouri RG, Ans AH, Akbar A, Toheed A. Recommendations for Anti-inflammatory Treatments in Alzheimer's Disease: A Comprehensive Review of the Literature. Cureus. 2019;11(5):e4620.
41. Potter PE. Investigational Medications for Treatment of Patients With Alzheimer Disease. J Am Osteopath Assoc. 2010;110:27-36.
42. Safieh M, Korczyn AD, Michaelson DM. ApoE4: an emerging therapeutic target for Alzheimer's disease. BMC Med. 2019;17(1):64.
43. Bokvist M, Lindstrom F, Watts A, Grobner G. Two types of Alzheimer's beta-amyloid (1-40) peptide membrane interactions: aggregation preventing transmembrane anchoring versus accelerated surface fibril formation. J Mol Biol. 2004;335(4):1039-49.
44. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, et al. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci. 2005;8(1):79-84.
45. Golde TE, Petrucelli L, Lewis J. Targeting Abeta and tau in Alzheimer's disease, an early interim report. Exp Neurol. 2010;223(2):252-66.
46. Lin SJ, Shiao YJ, Chi CW, Yang LM. Abeta aggregation inhibitors. Part 1: Synthesis and biological activity of phenylazo benzenesulfonamides. Bioorg Med Chem Lett. 2004;14(5):1173-6.
47. Liu D, Xu Y, Feng Y, Liu H, Shen X, Chen K, et al. Inhibitor Discovery Targeting the Intermediate Structure of β-Amyloid Peptide on the Conformational Transition Pathway: Implications in the Aggregation Mechanism of β-Amyloid Peptide. Biochemistry. 2006;45:10963-72.
48. Mancini RS, Wang Y, Weaver DF. Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation. Front Neurosci. 2018;12:735.
49. Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, et al. Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci. 2011;7(1):102-11.
50. Choi JS, Braymer JJ, Nanga RP, Ramamoorthy A, Lim MH. Design of small molecules that target metal-A{beta} species and regulate metal-induced A{beta} aggregation and neurotoxicity. Proc Natl Acad Sci U S A. 2010;107(51):21990-5.
51. Bareggi SR, Cornelli U. Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther. 2012;18(1):41-6. 52. Lee S, Carson K, Rice-Ficht A, Good T. Hsp20, a novel alpha-crystallin, prevents Abeta fibril formation and toxicity. Protein Sci. 2005;14(3):593-601.
53. Neddenriep B, Calciano A, Conti D, Sauve E, Paterson M, Bruno E, et al. Short Peptides as Inhibitors of Amyloid Aggregation. Open Biotechnol J. 2011;5:39-46.
54. Lemere CA. Developing novel immunogens for a safe and effective Alzheimer's disease vaccine. Neurotherapy: Progress in Restorative Neuroscience and Neurology. Progress in Brain Research2009. p. 83-93.
55. van Dyck CH. Anti-Amyloid-beta Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise. Biol Psychiatry. 2018;83(4):311-9.
56. Schenk D. Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning. Nat Rev Neurosci. 2002;3(10):824-8.
57. Watt AD, Crespi GA, Down RA, Ascher DB, Gunn A, Perez KA, et al. Do current therapeutic anti-Abeta antibodies for Alzheimer's disease engage the target? Acta Neuropathol. 2014;127(6):803-10.
58. Pickrell WO, Robertson NP. New treatments in Alzheimer's disease. J Neurol. 2018;265(9):2162-3.
59. Klein G, Delmar P, Kerchner GA, Hofmann C, Abi-Saab D, Davis A, et al. Thirty-Six-Month Amyloid Positron Emission Tomography Results Show Continued Reduction in Amyloid Burden with Subcutaneous Gantenerumab. J Prev Alzheimers Dis. 2021;8(1):3-6.
60. Tariot PN, Lopera F, Langbaum JB, Thomas RG, Hendrix S, Schneider LS, et al. The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer's disease, including a placebo-treated noncarrier cohort. Alzheimers Dement (N Y). 2018;4:150-60.
61. Vander Zanden CM, Chi EY. Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer's Disease. J Pharm Sci. 2020;109(1):68-73.
62. Ono K, Tsuji M. Protofibrils of Amyloid-beta are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease. Int J Mol Sci. 2020;21(3).
63. FDA Grants Accelerated Approval for Alzheimer’s Drug [press release]. FDA News Release: U.S. Food and Drug Administration, 07 Haziran 2021 2021.
64. FDA grants accelerated approval for ADUHELM™ as the first and only Alzheimer’s disease treatment to address a defining pathology of the disease [press release]. Biogen: Biogen Investor Relations, 7 Haziran 2021 2021.
65. Schneider A, Mandelkow E. Tau-Based Treatment Strategies in Neurodegenerative Diseases. The American Society for Experimental NeuroTherapeutics. 2008;5(3):443-57.
66. Gotz J, Ittner A, Ittner LM. Tau-targeted treatment strategies in Alzheimer's disease. Br J Pharmacol. 2012;165(5):1246-59.
67. Yoshiyama Y, Lee VM, Trojanowski JQ. Therapeutic strategies for tau mediated neurodegeneration. J Neurol Neurosurg Psychiatry. 2013;84(7):784-95.
68. Himmelstein DS, Ward SM, Lancia JK, Patterson KR, Binder LI. Tau as a therapeutic target in neurodegenerative disease. Pharmacol Ther. 2012;136(1):8-22.
69. Medina M. An Overview on the Clinical Development of Tau-Based Therapeutics. Int J Mol Sci. 2018;19(4).
70. Khanna MR, Kovalevich J, Lee VM, Trojanowski JQ, Brunden KR. Therapeutic strategies for the treatment of tauopathies: Hopes and challenges. Alzheimers Dement. 2016;12(10):1051-65.
71. Hong-Qi Y, Zhi-Kun S, Sheng-Di C. Current advances in the treatment of Alzheimer’s disease: focused on considerations targeting Aβ and tau. Translational Neurodegeneration. 2012;1(21).
72. Gao YL, Wang N, Sun FR, Cao XP, Zhang W, Yu JT. Tau in neurodegenerative disease. Ann Transl Med. 2018;6(10):175.
73. Pinheiro L, Faustino C. Alzheimer’s Disease & Treatment. MedDocs eBooks: MedDocs Publishers LLC; 2018.
74. Noble W, Jimenez-Sanchez M, Perez-Nievas BG, Hanger DP. Considerations for future tau-targeted therapeutics: can they deliver? Expert Opin Drug Discov. 2020;15(3):265-7.
75. Jadhav S, Avila J, Scholl M, Kovacs GG, Kovari E, Skrabana R, et al. A walk through tau therapeutic strategies. Acta Neuropathol Commun. 2019;7(1):22.
76. Brunden KR, Lee VM, Smith AB, 3rd, Trojanowski JQ, Ballatore C. Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs. Neurobiol Dis. 2017;105:328-35.
77. Brandt R, Bakota L. Microtubule dynamics and the neurodegenerative triad of Alzheimer's disease: The hidden connection. J Neurochem. 2017;143(4):409-17.
78. Pedersen JT, Sigurdsson EM. Tau immunotherapy for Alzheimer's disease. Trends Mol Med. 2015;21(6):394-402.
79. Hoskin JL, Sabbagh MN, Al-Hasan Y, Decourt B. Tau immunotherapies for Alzheimer's disease. Expert Opin Investig Drugs. 2019;28(6):545-54.
80. Pluta R, Ułamek-Kozioł M. Tau Protein-Targeted Therapies in Alzheimer’s Disease: Current State and Future Perspectives. In: Huang X, editor. Alzheimer’s Disease: Drug Discovery. Brisbane (AU): Exon Publications Copyright: The Authors.; 2020.
81. Bortolami M, Pandolfi F, De Vita D, Carafa C, Messore A, Di Santo R, et al. New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation. Eur J Med Chem. 2020;198:112350.
82. David B, Schneider P, Schafer P, Pietruszka J, Gohlke H. Discovery of new acetylcholinesterase inhibitors for Alzheimer's disease: virtual screening and in vitro characterisation. J Enzyme Inhib Med Chem. 2021;36(1):491-6.
83. Bautista-Aguilera OM, Ismaili L, Iriepa I, Diez-Iriepa D, Chabchoub F, Marco-Contelles J, et al. Tacrines as Therapeutic Agents for Alzheimer's Disease. V. Recent Developments. Chem Rec. 2021;21(1):162-74.
84. Yar M, Bajda M, Mehmood RA, Sidra LR, Ullah N, Shahzadi L, et al. Design and Synthesis of New Dual Binding Site Cholinesterase Inhibitors: in vitro Inhibition Studies with in silico Docking. Letters in Drug Design & Discovery. 2014;11(3):331-8.
85. Chen Y, Bian Y, Sun Y, Kang C, Yu S, Fu T, et al. Identification of 4-aminoquinoline core for the design of new cholinesterase inhibitors. PeerJ. 2016;4:e2140.
86. Alipour M, Khoobi M, Moradi A, Nadri H, Homayouni Moghadam F, Emami S, et al. Synthesis and anti-cholinesterase activity of new 7-hydroxycoumarin derivatives. European Journal of Medicinal Chemistry. 2014;82:536-44.
87. Li Q, Yang H, Chen Y, Sun H. Recent progress in the identification of selective butyrylcholinesterase inhibitors for Alzheimer's disease. Eur J Med Chem. 2017;132:294-309.
88. Kumar A, Nisha CM, Silakari C, Sharma I, Anusha K, Gupta N, et al. Current and novel therapeutic molecules and targets in Alzheimer's disease. J Formos Med Assoc. 2016;115(1):3-10.
89. Companys-Alemany J, Turcu AL, Bellver-Sanchis A, Loza MI, Brea JM, Canudas AM, et al. A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice. Pharmaceutics. 2020;12(3).
90. Liu J, Chang L, Song Y, Li H, Wu Y. The Role of NMDA Receptors in Alzheimer's Disease. Front Neurosci. 2019;13:43.
91. Zhang FQ, Jiang JL, Zhang JT, Niu H, Fu XQ, Zeng LL. Current status and future prospects of stem cell therapy in Alzheimer's disease. Neural Regen Res. 2020;15(2):242-50.
92. Lee JH, Oh IH, Lim HK. Stem Cell Therapy: A Prospective Treatment for Alzheimer's Disease. Psychiatry Investig. 2016;13(6):583-9.
93. Tong LM, Fong H, Huang Y. Stem cell therapy for Alzheimer's disease and related disorders: current status and future perspectives. Exp Mol Med. 2015;47:e151.
94. Duncan T, Valenzuela M. Alzheimer's disease, dementia, and stem cell therapy. Stem Cell Res Ther. 2017;8(1):111.
95. Nazem A, Mansoori GA. Nanotechnology Building Blocks for Intervention with Alzheimer’s Disease Pathology: Implications in Disease Modifying Strategies. Journal of Bioanalysis & Biomedicine. 2014;06(02).
96. Fonseca-Santos B, Gremiao MP, Chorilli M. Nanotechnology-based drug delivery systems for the treatment of Alzheimer's disease. Int J Nanomedicine. 2015;10:4981-5003.
97. Ansari SA, Satar R, Perveen A, Ashraf GM. Current opinion in Alzheimer's disease therapy by nanotechnology-based approaches. Current Opinion in Psychiatry. 2017;30(2):128-35.
98. Ahmad J, Akhter S, Rizwanullah M, Khan MA, Pigeon L, Addo RT, et al. Nanotechnology Based Theranostic Approaches in Alzheimer's Disease Management: Current Status and Future Perspective. Curr Alzheimer Res. 2017;14(11):1164-81.
99. Agrawal M, Saraf S, Saraf S, Antimisiaris SG, Hamano N, Li SD, et al. Recent advancements in the field of nanotechnology for the delivery of anti-Alzheimer drug in the brain region. Expert Opin Drug Deliv. 2018;15(6):589-617.
100. Wilson B, Geetha KM. Neurotherapeutic applications of nanomedicine for treating Alzheimer's disease. J Control Release. 2020;325:25-37.
101. Liu Y, Echeverria V, Xu Y. Editorial: Medicinal Plants for Cardiovascular and Neurodegenerative Aging-Related Diseases: From Bench to Bedside. Front Pharmacol. 2020;11:585155.
102. Wang T, Kuang W, Chen W, Xu W, Zhang L, Li Y, et al. A phase II randomized trial of sodium oligomannate in Alzheimer's dementia. Alzheimers Res Ther. 2020;12(1):110.