Ccr2-64i and Ccr5 Δ32 Polymorphisms in Patients with Late-Onset Alzheimer’s disease; A Study from Iran (Ccr2-64i And Ccr5 Δ32 Polymorphisms in Alzheimer’s disease)

Document Type: Original Article

Authors

1 Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

2 Reproductive Biotechnology Research Centre, Avicenna Research Institute (ACECR), Tehran, Iran

3 Epidemiology and Biostatistics Department, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Abstract

Objective(s)
Alzheimer’s disease (AD) is a complex disease with multifactorial etiology. Inflammation has been proven to have an important role in the pathogenesis of AD. Both CCR2 and CCR5 genes expression increase in AD patients comparing to control subjects. CCR5 gene encodes a protein which is a member of the beta chemokine receptors family of integral membrane proteins. CCR5-Δ32 is a genetic variant of CCR5 and is characterized by the presence of a 32-bp deletion in the coding region of the gene, which leads to the expression of a nonfunctional receptor, and the CCR2-64I has a change of valine to isoleucine at codon 64, in the first transmembrane domain. It has been proved that both genes have important roles in different stages of inflammation.
Materials and Methods
The frequencies of CCR5∆32 and CCR2-64I variations were determined in 156 AD patients and 161 control subjects using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods, and the results were compared among AD and healthy controls.
Results
Statistical analysis showed no significant difference in the distributions of CCR5∆32 and CCR2-64I between the AD patients and healthy controls (P> 0.05). Stratifying the samples by gender, genetic background and presence of ApoEε4 allele showed no significant effect on the distributions of CCR5∆32 and CCR2-64I        (P> 0.05).
Conclusion
Our study did not show an association between CCR5∆32 and CCR2-64I variations and AD in the Iranian population. Further confirmatory studies with bigger number of samples are recommended.

Keywords


1.  Selkoe DJ. Defining molecular targets to prevent Alzheimer’s disease. Arch Neurol 2005; 62: 192–195.

2. Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, Leon MJ. Inflammation and Alzheimer's disease: Possible role of periodontal diseases. Alzheimer Dement 2008; 4:242-250.

3. McGeer PL, McGeer EG. NSAIDs and Alzheimer’s disease: epidemiological, animal model and clinical studies. Neurobiol Aging 2007; 639-647.

4. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer’s disease progression: a randomized controlled trial. JAMA 2003; 289: 2819–2826.

5. Heneka MT, O’Banion MK. Inflammatory processes in Alzheimer’s disease. J. Neuroimmunol 2007; 184:69–91.

6. McGeer PL, Itagaki S, Tago H, McGeer EG. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987; 79:195–200.

7. Perlmutter LS, Barron E, Chui HC. Morphologic association between microglia and senile plaque amyloid in Alzheimer’s disease. Neurosci Lett  1990; 119:32–36.

8. Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella JK, et al. CD36, a Class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to b-amyloid fibrils. Am J Pathol  2002; 160:101–112.

9. El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, et al. CD36 mediates the innate host response to b-amyloid. J Exp Med  2003; 197:1657–1666.

10. Haga S, Ikeda K, Sato M, Ishii T. Synthetic Alzheimer amyloid beta/A4 peptides enhance production of complement C3 component by cultured microglial cells. Brain Res  1993; 601:88–94.

11. Moser B, Loetscher M, Piali L, Loetscher P. Lymphocyte responses to chemokines. Int Rev Immunol 1998; 16:323–344.

12. Zlotnik A,Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000; 12:121–127.

13. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol 2000; 18:217242.

14. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging  2000; 21:383-421.

15. Fantuzzi L, Borghi P, Ciolli V, Pavlakis G, Belardelli F, Gessani S. Loss Of  CCR2 expression and functional response to monocyte chemotactic protein (MCP-1) during the differentiation of human monocytes: role of secreted MCP-1 in the regulation of the chemotactic response. Blood 1999; 94:875-883.

16. Premack BA, Schall TJ. Chemokine receptors: gateways to inflammation and infection. Nat Med 1996, 2:1174-1178.

17. Baggiolini M. Chemokines and leukocyte traffic. Nature 1998, 392:565-568.

18. Mellado M, Rodriguez-Frade  JM, Vila-Coro AJ, Fernández S, Martín de Ana A, Jones DR, et al. Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J 2001; 20:2497–507.

19. El Khoury J, Toft M, Hickman SE, Means TK, Terada K. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med  2007; 13:432–438.

20. Zachariae CO, Anderson AO, Thompson HL, Appella E, Mantovani A, Oppenheim JJ, et al. Properties of monocyte chemotactic and activating factor (MCAF) purified from a human fibrosarcoma cell line. J Exp Med 1990; 171:2177–2182.

21. Viola A, Luster AD. Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol  2008; 48:171–197.

22.  Khoury JE, Luster AD.  Mechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications. Trends in Pharmacological Sciences?  2008; 29:626-632.

23. Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT. Immunohistochemical study of the -chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am J Pathol  1998; 153:31–37.

24. Man SM, Ma YR, Shang DS, Zhao WD, Li B, Guo DW, et al. Peripheral T cells overexpress MIP-1α  to enhance its transendothelial migration in Alzheimer’s disease. Neurobiol Aging 2007; 28:485-496.

25. Gharagozloo M, Doroudchi M, Farjadian S, Pezeshki AM, Ghaderi A. The frequency of CCR5Delta32 and CCR2-64I in Southern Iranian normal population. Immunol Lett 2005; 96:277-281.

 26. Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science 1997; 277:959 – 965.

27. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996; 367:77-86.

28.Galimberti D, Fenoglio C, Lovati C, Gatti A, Guidi I, Venturelli E, et al. CCR2-64I polymorphism and CCR5Delta32 deletion in patients with Alzheimer's disease. J Neurol Sci 2004; 225:79-83.

29. Huerta C, Alvarez V, Mata IF, Coto E, Ribacoba R, Martínez C, et al. Chemokines (RANTES and MCP-1) and chemokine-receptors (CCR2 and CCR5) gene polymorphisms in Alzheimer's and Parkinson's disease. Neurosci Lett 2004; 370:151-154.

30. Combarros O, Infante J, Llorca J, Peña N, Fernández-Viadero C, Berciano J. The chemokine receptor CCR5-Δ32 gene mutation is not protective against Alzheimer’s disease. Neurosci Lett 2004; 366:312-314.

31. Balistreri CR, Grimaldi MP, Vasto S, Listi F, Chiappelli M, Licastro F, et al. Association between the polymorphism of CCR5 and Alzheimer's disease: results of a study performed on male and female patients from Northern Italy. Ann N Y Acad Sci 2006; 1089:454-461.

32. Lampson LA. Molecular bases of the immune response to neural antigens. Trends Neuroscience; 10:211–216 1987.

33. Etminan M, Gill S, Samii A.Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: Systematic review and meta-analysis of observational studies. Bri Med J 2003; 327:128.

34. Hirsch EC, Hunot S, Damier P, Faucheux B. Glial cells and inflammation in Parkinson’s disease: A role in neurodegeneration? Ann Neurol 1998; 44:115–120.

35. Sorenson TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 1999; 103:801–815.

36. Mohaddes Ardebili SM, Rezazadeh M, Gharesouran J, Yeghaneh T, Farhoudi M, Ayromlou H, et al. Association of CCR2 gene but not CCR5 gene polymorphisms with Alzheimer’s disease. J Sci Islam Republic  Iran 2011; 22:111-116.