Cilt 24, Sayı 4, Sayfalar 178 - 187 2017-12-01

Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi (Kalsinörin ve Alzheimer Hastalığı)

Fatma Gonca Koçancı [1] , Belma Aslım [2]

47 82

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.

Alzheimer hastalığı,kalsinörin
  • Kaynaklar 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 Erişim tarihi Ekim 13, 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: 685692
  • 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, 6270-3.
  • 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 ioform of the regulatory subunit of CA2+/calmoduin-dependent protein phosphatase (calcineurinB2). 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, 16147‐54.
  • 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, 11728-34.
  • 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. Sci.1994; 747:1–11.
  • 18. O’Day DH, Myre MA. Calmodulin-binding domains in Alzheimer’s disease proteins: Extending the calcium hypothesisBiochem 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 Chem.1986; 261: 6084–6089.
  • 21. De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, Bigio EH, Jerecic J, Acton PJ, Shughrue PJ, Chen-Dodson E, Kinney GG, Klein WL. 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, Trojanowski JW. 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, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT. 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, McKeon F, Bobo T, Franke TF, Reed JC. 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, Landfield PW, Kraner SD. 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- a mini-review. 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, UK: Blackwell Scientific 1997; 172–188.
  • 42. McGeer E, McGeer P. Inflammatory cytokines in the CNS. CNS Drugs. 1997; 7:214–287. 43. Quintanilla R A, Orellana DI, Gonzalez-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-typephosphorylation 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, Scott JD. Science 1995; 267, 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, Henrique-Silva F, Crawford D, Canaider S, Strippoli P, Carinci P, Min KT, Fox DS, Cunningham KW, Bassel-Duby R, Olson EN, Zhang Z, Williams RS, Gerber HP, Pérez-Riba M, Seo H, Cao X, Klee CB, Redondo JM, Maltais LJ, Bruford EA, Povey S, Molkentin JD, McKeon FD, Duh EJ, Crabtree GR, Cyert MS, la Luna, de S, Estivill X. 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, Kellems RE, Xia Y. 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, Liu QF, Lee IS, Cho KS. 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-kappaB, 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, Inagaki M, Urushihara N, Yagi T, Tanaka N. Calcineurin antagonists inhibit interferon-gamma production by downregulation of interleukin-18 in human mixed lymphocyte reactions. Acta Med Okayama. 2000; 54(5): 201-9.
  • 55. Tsuda K, Yamanaka K, Kitagawa, H, Akeda T, Naka M, Niwa K, Nakanishi T, Kakeda M, Gabazza EC, Mizutani H. Calcineurin Inhibitors Suppress Cytokine Production from Memory T Cells and Differentiation of Naïve T Cells into Cytokine-Producing Mature T Cells. PLoS One. 2012; 7(2): e31465.
  • 56. Ramos S, Butler L, Kimbler T, Cao J, Grey J, Rogers E, Wang Z, Whitten J, Roos J, Stauderman K, Velicelebi G. 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.
Konular Tıp Bilimleri
Dergi Bölümü Derlemeler
Yazarlar

Yazar: Fatma Gonca Koçancı
E-posta: goncaok@gmail.com

Yazar: Belma Aslım
E-posta: baslim@gazi.edu.tr

Bibtex @derleme { sdutfd359977, journal = {SDÜ Tıp Fakültesi Dergisi}, issn = {1300-7416}, address = {Süleyman Demirel Üniversitesi}, year = {2017}, volume = {24}, pages = {178 - 187}, doi = {}, title = {Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi (Kalsinörin ve Alzheimer Hastalığı)}, language = {tr}, key = {cite}, author = {Koçancı, Fatma Gonca and Aslım, Belma} }
APA Koçancı, F , Aslım, B . (2017). Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi (Kalsinörin ve Alzheimer Hastalığı). SDÜ Tıp Fakültesi Dergisi, 24 (4), 178-187. Retrieved from http://dergipark.gov.tr/sdutfd/issue/32300/359977
MLA Koçancı, F , Aslım, B . "Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi (Kalsinörin ve Alzheimer Hastalığı)". SDÜ Tıp Fakültesi Dergisi 24 (2017): 178-187 <http://dergipark.gov.tr/sdutfd/issue/32300/359977>
Chicago Koçancı, F , Aslım, B . "Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi (Kalsinörin ve Alzheimer Hastalığı)". SDÜ Tıp Fakültesi Dergisi 24 (2017): 178-187
RIS TY - JOUR T1 - Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi (Kalsinörin ve Alzheimer Hastalığı) AU - Fatma Gonca Koçancı , Belma Aslım Y1 - 2017 PY - 2017 N1 - DO - T2 - SDÜ Tıp Fakültesi Dergisi JF - Journal JO - JOR SP - 178 EP - 187 VL - 24 IS - 4 SN - 1300-7416-2602-2109 M3 - UR - Y2 - 2017 ER -
EndNote %0 SDÜ Tıp Fakültesi Dergisi Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi (Kalsinörin ve Alzheimer Hastalığı) %A Fatma Gonca Koçancı , Belma Aslım %T Kalsinörin Mekanizması ve Kalsinörin İnhibitörlerinin Alzheimer Hastalığının Tedavisindeki Önemi (Kalsinörin ve Alzheimer Hastalığı) %D 2017 %J SDÜ Tıp Fakültesi Dergisi %P 1300-7416-2602-2109 %V 24 %N 4 %R %U