ERKEN VE GEÇ BAŞLANGIÇLI ALZHEIMER HASTALARININ PERİFERİK KANLARINDA SEÇİLMİŞ miRNA’LARIN ANLATIM DÜZEYİ

Yıl 2021, , 165 - 174, 25.04.2021

Gamze Güven Ebba Lohmann Çağrı Güleç Başar Bilgiç Ebru Özer Haşmet Hanağası Hakan Gürvit Nihan Ünaltuna

https://doi.org/10.26650/IUITFD.2020.0061

Öz

Amaç: Enflamasyon ve ilişkili mikro RNA’lar (miRNA), Alzheimer hastalığının (AH) patogenezinde önemli rol oynamaktadırlar. AH beyininde görülen miRNA’ların anlatım profilindeki değişikliklerin periferal kan mononükleer hücrelerine de yansımış olması, AH sırasında görülen enflamatuar değişikliklerin bir göstergesi olabilir. Bu çalışmada, Alzheimer hastalarının hem periferal lökositlerinde hem de plazmalarında belirli enflamatuvar miRNA’ların (mir-146a, mir-144, mir-34a) anlatım düzeylerindeki değişiklikleri araştırmayı ve ve AH tanısında biyobelirteç olarak potansiyel kullanılabilirliklerini değerlendirmek. Ayrıca, bu miRNA’ların anlatımlarının erken ve geç başlangıçlı AH arasında farklılık gösterip göstermediğini belirlemeyi amaçladık. Gereç ve Yöntem: Gerçek zamanlı polimeraz zincir reaksiyonu yöntemini kullanarak 16 erken başlangıçlı ve 26 geç başlangıçlı AH hastası ve yaş-uyumlu kontrollerinde miRNA’ların anlatım düzeylerini araştırdık. Bulgular: Plazma mir-144 anlatım düzeyinin erken ve geç başlangıçlı AH hastaları arasında anlamlı farklılık gösterdiğini saptadık (p = 0.015). Ek olarak, lökosit mir-34a anlatım düzeyi erken başlangıçlı AH’de geç başlangıçlı AH hastalarına göre anlamlı derecede düşük bulundu (p = 0.027). Sonuçlarımız ayrıca, yaş ve plazma mir-144 (r=0.319, p=0.02) ile lökosit mir-34a (r=0.414, p=0.001) anlatım düzeyleri arasında anlamlı pozitif korelasyon olduğunu gösterdi. Sonuç: Bulgularımız erken ve geç başlangıçlı AH hastaları arasında plazma mir-144 ve lökosit mir-34a anlatımlarında görülen farklılığın miRNA ekspresyonundaki yaşa bağlı değişiklikleri yansıttığını ve hastalık durumundan bağımsız olabileceğini düşündürmektedir.

Anahtar Kelimeler

Alzheimer hastalığı, miRNA, miRNA anlatımı

Destekleyen Kurum

Bu çalışma İstanbul Üniversitesi Bilimsel Araştırma Projeleri kapsamında desteklenmiştir

Proje Numarası

48601

EXPRESSION OF SELECTED miRNAs IN CIRCULATING BLOOD OF EARLY AND LATE-ONSET ALZHEIMER DISEASE PATIENTS

Öz

Objective: Inflammation and associated microRNAs (miRNA) both play essential roles in the pathogenesis of Alzheimer’s disease (AD). The expression profile of miRNA’s in an AD brain, also reflected in the peripheral blood mononuclear cells, may give support to the inflammatory changes seen in the course of AD. We aimed to investigate the expression levels of specific inflammatory miRNAs (mir-146a, mir-144, mir-34a) in both blood leukocytes and plasma of AD patients and to evaluate their potential usability as biomarkers in AD diagnosis and to also demonstrate whether the expression of these miRNAs differ between early and late-onset AD patients. Methods: We investigated the expression levels of miRNAs in 16 early-onset and 26 late-onset AD patients and in their respective controls by using qRT-PCR. Results: Plasma mir-144 levels were significantly different between EOAD and LOAD patients (p=0.015). In addition, levels of leukocyte mir-34a were significantly down-regulated in EOAD compared to LOAD patients (p=0.027). Our results also showed significant positive correlations between age and plasma mir- 144 and leukocyte mir-34a expressions. Conclusion: The differential expression of plasma mir-144 and leukocyte mir-34a between EOAD and LOAD patients might reflect age-dependent changes in miRNA expression and might be independent of the disease status.

Anahtar Kelimeler

Alzheimer disease, miRNA, miRNA expression

Proje Numarası

48601

Kaynakça

• 1. O’Carroll D, Schaefer A. General principals of miRNA biogenesis and regulation in the brain. Neuropsychopharmacology 2013;(38):39–54. [CrossRef]
• 2. Li Y, Kowdley KV. MicroRNAs in common human diseases. Genomics Proteomics Bioinformatics 2012;10(5):246-253. [CrossRef]
• 3. Wang M, Qin L, Tang B. MicroRNAs in Alzheimer’s Disease. Front Genet 2019;(10):153. [CrossRef]
• 4. Swarbrick S, Wragg N, Ghosh S, Stolzing A. Systematic Review of miRNA as Biomarkers in Alzheimer’s Disease. Mol Neurobiol 2019;56(9):6156–67. [CrossRef]
• 5. Schipper HM, Maes OC, Chertkow HM, Wang E. MicroRNA expression in Alzheimer blood mononuclear cells. Gene Regul Syst Bio 2007;1:263-74. [CrossRef]
• 6. Taganov KD, Boldin MP, Chang KJ, Baltimore D. NFkappaB- dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 2006;103(33):12481-6. [CrossRef]
• 7. Cheng C, Li W, Zhang Z, Yoshimura S, Hao Q, Zhang C et al. MicroRNA-144 is regulated by activator protein-1 (AP-1) and decreases expression of Alzheimer disease-related a disintegrin and metalloprotease 10 (ADAM10). J Biol Chem 2013;288(19):13748-61. [CrossRef]
• 8. Zhao Y, Bhattacharjee S, Jones BM, Dua P, Alexandrov PN, Hill JM, et al. Regulation of TREM2 expression by an NF- кB-sensitive miRNA-34a. Neuroreport 2013;24(6):318-23. [CrossRef]
• 9. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7(3):263-9. [CrossRef]
• 10. Bhatnagar S, Chertkow H, Schipper HM, Yuan Z, Shetty V, Jenkins S, Jones T, Wang E. Increased microRNA-34c abundance in Alzheimer’s disease circulating blood plasma. Front Mol Neurosci 2014;7:2. [CrossRef]
• 11. Andersen CL, Ledet-Jensen J, Ørntoft T. Normalization of real-time quantitative RT-PCR data: a model based variance estimation approach to identify genes suited for normalization - applied to bladder- and colon-cancer datasets. Cancer Research 2004;64:5245-50. [CrossRef]
• 12. Pfaffl MW, Tichopád A, Prgomet C, Neuvians TP. Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper – Excel-based tool using pair-wise correlations. Biotechnology Letters 2004;26(6):509-15. [CrossRef]
• 13. Huang RS, Gamazon ER, Ziliak D, Wen Y, Im HK, Zhang W, et al. Population differences in microRNA expression and biological implications. RNA Biology 2011;8(4):692-701. [CrossRef]
• 14. Alexandrov PN, Dua P, Hill JM, Bhattacharjee S, Zhao Y, Lukiw WJ. microRNA (miRNA) speciation in Alzheimer’s disease (AD) cerebrospinal fluid (CSF) and extracellular fluid (ECF). Int J Biochem Mol Biol 2012;3(4):365–73.
• 15. Lukiw WJ, Alexandrov PN, Zhao Y, Hill JM, Bhattacharjee S. Spreading of Alzheimer’s disease inflammatory signaling through soluble micro-RNA. Neuroreport 2012;23(10):621- 26. [CrossRef]
• 16. Müller M, Kuiperij HB, Claassen JA, Kusters B, Verbeek MM. MicroRNAs in Alzheimer’s disease: Differential expression in hippocampus and cell-free cerebrospinal fluid. Neurobiol Aging 2014;35(1):152-8. [CrossRef]
• 17. Lusardi TA, Phillips JI, Wiedrick JT, Harrington CA, Lind B, Lapidus JA et al. MicroRNAs in human cerebrospinal fluid as biomarkers for Alzheimer’s disease. J Alzheimers Dis 2017; 55(3):1223–33. [CrossRef]
• 18. Manzine PR, Pelucchi S, Horst MA, Vale FAC, Pavarini SCI, Audano M et al. MicroRNA 221 targets ADAM10 mRNA and is downregulated in Alzheimer’s disease. J Alzheimers Dis 2018;61(1):113–23. [CrossRef]
• 19. Dias IHK, Brown CL, Shabir K, Polidori MC, Griffiths HR. miRNA 933 expression by endothelial cells is increased by 27- hydroxycholesterol and is more prevalent in plasma from dementia patients. J Alzheimers Dis.2018;64(3):1009– 17. [CrossRef]
• 20. Wu Y, Xu J, Xu J, Cheng J, Jiao D, Zhou C, Dai Y, Chen Q. Lower Serum Levels of miR-29c-3p and miR-19b-3p as Biomarkers for Alzheimer’s Disease. The Tohoku journal of experimental medicine 2017;242(2):129–36. [CrossRef]
• 21. Yılmaz ŞG, Erdal ME, Özge AA, Sungur MA. Can Peripheral MicroRNA Expression Data Serve as Epigenomic (Upstream) Biomarkers of Alzheimer’s Disease? OMICS 2016;20(8):456- 61. [CrossRef]
• 22. Li YY, Cui JG, Hill JM, Bhattacharjee S, Zhao Y, Lukiw WJ. Increased expression of miRNA-146a in Alzheimer’s disease transgenic mouse models. Neurosci Lett 2011;487(1):94-8. [CrossRef]
• 23. Lukiw WJ, Zhao Y, Cui JG. An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 2008;283(46):31315-22. [CrossRef]
• 24. Sethi P, Lukiw WJ. Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer’s disease temporal lobe neocortex. Neurosci Lett 2009;459(2):100-4. [CrossRef]
• 25. Denk J, Boelmans K, Siegismund C, Lassner D, Arlt S, Jahn H. MicroRNA profiling of CSF reveals potential biomarkers to detect Alzheimer’s disease. PLoS One 2015;10(5):e0126423. [CrossRef]
• 26. Kiko T, Nakagawa K, Tsuduki T, Furukawa K, Arai H, Miyazawa T. MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer’s disease. J Alzheimers Dis 2014;39(2):253–9. [CrossRef]
• 27. Cosín-Tomás M, Antonell A, Lladó A, Alcolea D, Fortea J, Ezquerra M, et al. Plasma miR-34a-5p and miR-545-3p as Early Biomarkers of Alzheimer’s Disease: Potential and Limitations. Mol Neurobiol 2017;54(7):5550-62. [CrossRef]
• 28. Dong H, Li J, Huang L, Chen X, Li D, Wang T, et al. Serum MicroRNA Profiles Serve as Novel Biomarkers for the Diagnosis of Alzheimer’s Disease. Dis Markers 2015;2015:625659. [CrossRef]
• 29. Maffioletti E, Milanesi E, Ansari A, Zanetti O, Galluzzi S, Geroldi C, et al. miR-146a Plasma Levels Are Not Altered in Alzheimer’s Disease but Correlate With Age and Illness Severity. Front Aging Neurosci 2020;11:366. [CrossRef]
• 30. Satoh J, Kino Y, Niida S. MicroRNA-Seq Data Analysis Pipeline to Identify Blood Biomarkers for Alzheimer’s Disease from Public Data. Biomark Insights 2015;10:21-31. [CrossRef]
• 31. Persengiev S, Kondova I, Otting N, Koeppen AH, Bontrop RE. Genome-wide analysis of miRNA expression reveals a potential role for miR-144 in brain aging and spinocerebellar ataxia pathogenesis. Neurobiol Aging 2011;32(12):2316. e17-27. [CrossRef]
• 32. Persengiev SP, Kondova II, Bontrop RE. The Impact of MicroRNAs on Brain Aging and Neurodegeneration. Curr Gerontol Geriatr Res 2012;2012:359369. [CrossRef]
• 33. Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, et al. Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 2008;14(1):27-41. [CrossRef]
• 34. Sarkar S, Jun S, Rellick S, Quintana DD, Cavendish JZ, Simpkins JW. Expression of microRNA-34a in Alzheimer’s disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Brain Res 2016;1646:139-151. [CrossRef]
• 35. Owczarz M, Budzinska M, Domaszewska-Szostek A, Borkowska J, Polosak J, Gewartowska M, et al. miR- 34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans. Exp Biol Med (Maywood) 2017;242(14):1453- 61. [CrossRef]