Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi

Fatma Gonca Koçancı; Belma Aslım

doi:10.17343/sdutfd.263872

Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi

Öz

Alzheimer hastalığı (AH), hafızanın sürekli bir şekilde azalması ile karakterize olan, tedavi edilemeyen, yaşa bağlı nörodejeneratif bir hastalıktır. AH’nin nedenleri tam olarak açıklanamamış olsa da, tau proteinlerinin hiperfosforilasyonunun, mikrotübül stabilizasyonun ve iyon dengesinin bozulmasının, inflamasyon oluşumunun ve apoptozun AH ile ilişkili olduğu bilinmektedir. AH tedavisi için hali hazırda geliştirilen ilaçlar olmasına rağmen, bunlar ancak semptomları yavaşlatarak hastalığın ilerlemesini geciktirmektedir. Mevcut ilaçların klinik çalışmalarda ve pratikte yararları minimaldir ve hiçbiri tam anlamıyla bir tedavi sağlayamamaktadır. Bu nedenle, AH üzerinde etkili olacak koruyucu ve tedavi edici potansiyeli olan yeni ajanların belirlenme çalışmaları önemli bir araştırma alanı haline gelmiştir. Bir treonin ve serin protein fosfataz olan kalsinörinin, AH’de hiperaktivasyonunu kanıtlayan in vitro, ex vivo ve hayvan modellerine ilişkin bilgiler giderek artmaktadır. Bu derleme, kalsinörin mekanizmasını, AH’de görülen kalsinörinin hiperaktivitesine ait kanıtları ve AH tedavisinde bir umut ışığı olarak kalsinörin inhibitörlerinin bellek onarımında, anti-inflamasyonda, tau defosforilasyonunda ve anti-apoptozda nasıl etki ettiğine dair ayrıntıları içermektedir.

Anahtar Kelimeler

Alzheimer hastalığı,kalsinörin,kalsinörin inhibitörleri

Kaynakça

1. Lieo A, Greenberg S, Growdon J. Current pharmacotherapy for Alzheimer's disease. Annu Rev Med 2006; 57: 513–533.
2. World Alzheimer Report 2015: The global impact of dementia. https://www.alz.co.uk/research/world-report-2015 (ET: 13.10.2016).
3. Teri L, Logsdon, RG, McCurry SM. Nonpharmacological treatment of behavioral disturbance in dementia. Medical Clinics of North America 2002; 86: 641-656.
4. Ulger Z, Yavuz BB, Halil M, Cankurtaran M, Arıoğul S. Alzheimer hastalığı tedavisinde kullanılan ilaçlar. Akademik Geriatri Dergisi 2009; 1 (1): 3-12.
5. Reese LC, Taglialatela G. A role for calcineurin in Alzheimer’s disease Curr Neuropharmacol 2011; 9: 685-692.
6. Klee CB, Crouch TH, Krinks MH. Calcineurin: a calcium and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci U S A. 1979; 76 (12): 6270-6273.
7. Qin Y, Yu D, Wei Q. Function and structure of recombinant single chain calcineurin. Biochem Biophys Res Commun 2003; 308(1): 87-93.
8. Dammann H, Hellstern S, Husain Q, Mutzel R. Primary structure, expression and developmental regulation of a Dictyostelium calcineurin A homolog. Eur J Biochem 1996; 238: 391–399.

9. Chang CD, Mukai H, Kuno T, Tanaka C. cDNA cloning of an alternatively spliced isoform of the regulatory subunit of CA2+/calmoduin-dependent protein phosphatase (calcineurin B alpha 2) Biochem Biophys Acta 1994; 1217:174-180.
10. Yang SA, Klee CB. Low affinity Ca2+‐binding sites of calcineurin B mediate conformational changes in calcineurin A. Biochemistry 2000; 39 (51): 16147‐16154.
11. Namgaladze D, Shcherbyna I, Kienhofer J, Werner Hofer H, Ullrich V. Superoxide targets calcineurin sigmalling in vascular endothelium. Biochim Biophys Res Commun 2005; 334: 1061-1067.
12. Tokoyoda K, Takemoto Y, Nakayama T, Arai T, Kubo M. Synergism between the calmodulin-binding and autoinhibitory domains on calcineurin is essential for the induction of their phosphatase activity. J Biol Chem 2000; 275 (16): 11728-11734.
13. Klee CB, Krinks MH. Purification of cyclic 39, 59-nucleotide phosphodiesterase inhibitory protein by affinity chromatography on activator protein coupled to Sepharose. Biochemistry 1978; 17: 120–126.
14. Wallace RW, Lynch TJ, Tallant EA, Cheung WY. Purification and characterization of an inhibitor protein of brain adenylate cyclase and cyclic nucleotide phosphodiesterase. J Biol Chem 1978; 254: 377–382.
15. Aramburu J, Rao A, Klee CB. Calcineurin: from structure to function. Curr Top Cell Regul 2000; 36: 237–295.
16. Roth M, Tomlinson BE, Blessed G. Correlation between scores for dementia and counts of “senile plaques” in cerebral grey matter of elderly subjects. Nature 1966; 209:109–110.
17. Khachaturian ZS. Calcium hypothesis of Alzheimer's disease and brain aging. Ann N Y Acad Sci1994; 747: 1–11.
18. O’Day DH, Myre MA. Calmodulin-binding domains in Alzheimer’s disease proteins: Extending the calcium hypothesis. Biochem Biophys Res Commun 2004; 230: 1051-1054.
19. Lian QY, Ladner CJ, Magnuson D, Lee JM. Selective changes of calcineurin (protein phosphatase 2B) activity in Alzheimer's disease cerebral cortex. Exp Neurol 2001; 167:158–165.
20. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem1986; 261: 6084–6089.
21. De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, et al. Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers. Neurobiol Aging 2008; 29: 1334–1347.
22. Qian W, Yin X, Hu W, Shi J, Gu J, Iqbal IG. Activation of protein phosphatase 2B and hyperphosphorylation of tau in Alzheimer's disease. Alzheimers Dis 2011; 23(4): 617–627.
23. Billingsley ML, Ellis C, Kincaid RL, Martin J, Schmidt ML, Lee VMY, et al. Calcineurin immunoreactivity in Alzheimers-disease. Exp Neurol 1994; 126: 178-184.
24. De Strooper B, Annaert W. Proteolytic processing and cell biological functions of the amyloid precursor protein. Journal of Cell Science 2000; 113: 1857-1870.
25. Mohandas E, Rajmohan V, Raghunath B. Neurobiology of Alzheimer's disease. Ind J Psychiatry 2009; 51: 55–61.
26. Agostinho P, Oliveira C. Involvement of calcineurin in the neurotoxic effects induced by amyloid-beta and prion peptides. Eur J Neurosci 2003; 17: 1189–1196.
27. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, et al. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 2010; 30: 2636–2649.
28. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999; 284: 339-343.
29. Wisniewski HM, Terry RD. Morphology of the aging brain, human and animal. Prog Brain Res 1973; 40:167–186.
30. Eddleston M, Mucke L. Molecular profile of reactive astrocytes-implications for their role in neurologic disease. Neuroscience 1993; 54:15–36.
31. Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 1997; 20: 570–577.
32. Norris CM, Kadish I, Blalock EM, Chen KC, Thibault V, Porter NM, et al. Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer’s models. The Journal of Neuroscience 2005; 25: 4649-4658.
33. Landfield PW, Campbell LW, Hao SY, Kerr DS. Aging-related increases in voltage-sensitive, inactivating calcium currents in rat hippocampus. Implications for mechanisms of brain aging and Alzheimer’s disease. Ann NY Acad Sci 1989; 568: 95–105.
34. Williams CR, Gooch JL. Calcineurin inhibitors and immunosuppression - a tale of two isoforms. Expert Rev Mol Med 2012; 4 (14): e14.
35. Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu. Rev Immunol 1997; 15: 707-747.
36. Chow CW, Rincon M, Davis RJ. Requirement for transcription factor NFAT in interleukin-2 expression. Mol Cell Bioi 1999; 19: 2300-2307.
37. Phul RK, Shaw PJ, Ince PG, Smith ME. Expression of nitric oxide synthase isoforms in spinal cord in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 2000; 1(4): 259-267. doi:10.1080/14660820050515089.
38. Gruol DL, Nelson TE. Physiological and pathological roles of interleukin- 6 in the central nervous system. Mol Neurobiol 1997; 15: 307–339.
39. Cacabelos R, Barquero M, Garcia P, Alvarez XA, Varela de Seijas E. Cerebrospinal fluid interleukin-1beta (IL-1beta) in Alzheimer’s disease and neurological disorders. Methods Find Exp Clin Pharmacol 1991; 13: 455– 458.
40. McNaull BB, Todd S, McGuinness B, Passmore AP. Inflammation and anti-inflammatory strategies for Alzheimer's disease. Gerontology 2010; 56: 3-14.
41. Walker D, McGeer E, McGeer P. Involvement of inflammation and complement in Alzheimer’s disease. In: Antel J, Birnbaum G, Härtung H, editors. Clinical Neuroimmunology Oxford, Blackwell Scientific 1997; 172–188.
42. McGeer E, McGeer P. Inflammatory cytokines in the CNS. CNS Drugs 1997; 7: 214–287.
43. Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 2004; 295: 245–257. doi: 10.1016/j.yexcr.2004.01.002.
44. Coghlan VM, Perrino BA, Howard M, Langeberg LK, Hicks JB, Gallatin WM, et al. Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. Science 1995; 267 (5194): 108-111.
45. Sun L, Youn HD, Loh C, Stolow M, He W, Liu JO. Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 1998; 8(6): 703–711.
46. Crabtree GR. Calcium, calcineurin and the control of transcription. J Biol Chem 2001; 276: 2313-2316.
47. Miskin JE, Abrams CC, Goatley LC, Dixon LK. A viral mechanism for inhibition of the cellular phosphatase calcineurin. Science 1998; 281: 562–565.
48. Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, et al. Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. The FASEB Journal 2007; 21: 3023–3028.
49. Abbasi S, Lee JD, Su B, Chen X, Alcon JL, Yang J, et al. Protein kinase-mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin-interacting protein 1. J Biol Chem 2006; 281: 7717-7726.
50. Shin SY, Yang HW, Kim JR, Heo WD, Cho KH. A hidden incoherent switch regulates RCAN1 in the calcineurin-NFAT signaling network. J Cell Sci 2011; 124: 82–90. doi: 10.1242/jcs.076034.
51. Lee S, Bang SM, Hong YK, Lee JH, Jeong H, Park SH, et al. The calcineurin inhibitor Sarah (Nebula) exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease. Dis Model Mech 2016; 9 (3): 295-306. doi: 10.1242/dmm.018069.
52. Aoki Y, Kao PN. Erythromycin inhibits transcriptional activation of NF-kappa B, but not NFAT, through calcineurin-independent signaling in T cells. Antimicrob Agents Chemother 1999; 43: 2678–2684.
53. Dineley KT, Hogan D, Zhang WR, Taglialatela G. Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem 2007; 88: 217-224.
54. Kuinose M, Iwagaki H, Morimoto Y, Kohka H, Kobashi K, Sadamori H, et al. Calcineurin antagonists inhibit interferon-gamma production by downregulation of interleukin-18 in human mixed lymphocyte reactions. Acta Med Okayama 2000; 54(5): 201-209.
55. Tsuda K, Yamanaka K, Kitagawa, H, Akeda T, Naka M, Niwa K, et al. Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of Native T cells into cytokine-producing mature T cells. PLoS One 2012; 7(2): e31465. doi:10.1371/journal.pone.0031465.
56. Ramos S, Butler L, Kimbler T, Cao J, Grey J, Rogers E, et al. CRAC channel inhibitors block cytokine production with a pattern distinguishable from cyclosporine (P5216). The Journal of Immunology 2013; 190 (1 Supplement): 212.5.
57. Halloran PF, Helms LM, Kung L, Noujaim J. The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation 1999; 68: 1356-1361.
58. Taglialatela G, Rastellini C, Cicalese L. Reduced incidence of dementia in solid organ transplant patients treated with calcineurin inhibitors. J Alzheimers Dis 2015; 47 (2): 329-333.

Ayrıntılar

Birincil Dil

İngilizce

Konular

Klinik Tıp Bilimleri

Bölüm

Derleme

Yazarlar

Fatma Gonca Koçancı
Gazi Üniversitesi
Türkiye

Belma Aslım
Gazi Üniversitesi
Türkiye

Yayımlanma Tarihi

1 Aralık 2017

Gönderilme Tarihi

27 Aralık 2016

Kabul Tarihi

-

Yayımlandığı Sayı

Yıl 2017 Cilt: 24 Sayı: 4

DOI

https://doi.org/10.17343/sdutfd.263872

IZ

https://izlik.org/JA56EC27LZ

Kaynak Göster

RIS / Bibtex

APA

Koçancı, F. G., & Aslım, B. (2017). Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi. Medical Journal of Süleyman Demirel University, 24(4), 178-187. https://doi.org/10.17343/sdutfd.263872

AMA

1.Koçancı FG, Aslım B. Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi. SDÜ Tıp Fak Derg. 2017;24(4):178-187. doi:10.17343/sdutfd.263872

Chicago

Koçancı, Fatma Gonca, ve Belma Aslım. 2017. “Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi”. Medical Journal of Süleyman Demirel University 24 (4): 178-87. https://doi.org/10.17343/sdutfd.263872.

EndNote

Koçancı FG, Aslım B (01 Aralık 2017) Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi. Medical Journal of Süleyman Demirel University 24 4 178–187.

IEEE

[1]F. G. Koçancı ve B. Aslım, “Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi”, SDÜ Tıp Fak Derg, c. 24, sy 4, ss. 178–187, Ara. 2017, doi: 10.17343/sdutfd.263872.

ISNAD

Koçancı, Fatma Gonca - Aslım, Belma. “Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi”. Medical Journal of Süleyman Demirel University 24/4 (01 Aralık 2017): 178-187. https://doi.org/10.17343/sdutfd.263872.

JAMA

1.Koçancı FG, Aslım B. Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi. SDÜ Tıp Fak Derg. 2017;24:178–187.

MLA

Koçancı, Fatma Gonca, ve Belma Aslım. “Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi”. Medical Journal of Süleyman Demirel University, c. 24, sy 4, Aralık 2017, ss. 178-87, doi:10.17343/sdutfd.263872.

Vancouver

1.Fatma Gonca Koçancı, Belma Aslım. Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi. SDÜ Tıp Fak Derg. 01 Aralık 2017;24(4):178-87. doi:10.17343/sdutfd.263872

Cited By

Role of calcineurin and ionotropic glutamate receptors in Alzheimer's disease: A systematic review

Brain Disorders

https://doi.org/10.1016/j.dscb.2025.100218