Peripheral Expression Levels of Selected Oxidative Stress-Related Genes in Alzheimer’s Disease

Abstract

Objective: The etiology of Alzheimer's disease (AD) is affected via oxidative stress. Antioxidant enzymes are extremely important in preventing reactive oxygen species (ROS) causing damage in the cell. The changes in expression levels of oxidant and antioxidant genes are key factors in cell response to oxidative stress. As a result, this study investigated the change in expression levels of specif-ic oxidative stress related genes (solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), catalase (CAT ) and acyl-coa synthetase long chain family member 4 (ACSL4)) in peripheral blood of AD patients.

Material and Method: Quantitative reverse-transcription poly-merase chain reaction (qRT-PCR) was used to assess the expression levels of oxidative stress-related genes in 25 AD patients and 22 controls, and the findings were statistically evaluated.

Results:SLC7A11, GPX4, CAT, and ACSL4 gene expression levels did not vary significantly between AD patients and controls. The re-sults also showed significant negative correlation between age of onset and ACSL4 expression.

Conclusion: This is the first study that evaluated mRNA expression levels of SLC7A11, GPX4 and ACSL4 genes in AD. The results sug-gested that the peripheral blood expression of above-mentioned genes did not alter in AD. However, due to the small number of subjects, this findings are preliminary and should be validated with a larger number of subjects.

Keywords

• Alzheimer’s Disease
• oxidative stress
• SLC7A11
• GPX4
• CAT
• ACSL4

Alzheimer Hastalığında Oksidatif Stres ile İlişkili Seçilmiş Genlerin Periferik Kandaki Anlatım Düzeyi

Abstract

Amaç: Oksidatif stres, Alzheimer hastalığının (AH) etiyolojisinde önemli bir rol oynamaktadır. Antioksidan enzimler reaktif oksijen türevlerinin (ROS) hücreye zarar vermesini önlemek için çok önemlidir. Oksidan ve antioksidan enzimleri kodlayan genlerin anlatım seviyelerindeki değişimler hücrenin oksidatif strese karşı verdiği yanıtta anahtar faktördür. Bu nedenle çalışmamızda, AH hastalarının periferik kanlarında spesifik oksidatif stres ile ilişkili genlerin (solut taşıyıcı aile 7 üye 11 (SLC7A11), glutatyon peroksidaz 4 (GPX4), katalaz (CAT ) ve açil koA sentetaz uzun zincir aile üyesi 4 (ACSL4)) anlatım düzeylerindeki değişimin araştırılması amaçlanmıştır.

Gereç ve Yöntem: Periferik kan lökositlerinde oksidatif stresle ilgili genlerin ekspresyon düzeylerindeki değişiklikler 25 AH hastası ve 22 kontrolde kantitatif ters transkripsiyon polimeraz zincir reaksiyonu (qRT-PCR) ile belirlenmiş ve sonuçlar istatistiksel olarak değerlendirilmiştir.

Bulgular:SLC7A11, GPX4, CAT ve ACSL4 genlerinin anlatım düzeyleri, AH hastaları ve kontroller arasında istatistiksel olarak bir farklılık göstermemiştir. Ayrıca, sonuçlarımız başlangıç yaşı ile ACSL4 ekspresyonu arasında anlamlı negatif bir korelasyon olduğunu göstermiştir.

Sonuç: Araştırmamız, AH hastalarının periferik kanlarında SLC7A11, GPX4 ve ACSL4 genlerinin anlatım düzeylerini değerlendiren ilk çalışma olup, sonuçlarımız söz konusu genlerin periferik kandaki an-latımlarının AH'de değişmediğini göstermiştir. Bununla birlikte, az sayıda hasta ve kontrol nedeniyle, bu bulgular başlangıç niteliğindedir ve daha geniş çalışma gruplarında doğrulanması gerekmektedir.

Keywords

• Alzheimer hastalığı
• oksidatif stres
• SLC7A11
• GPX4
• CAT
• ACSL4

References

1. 1. Mantzavinos V, Alexiou A. Biomarkers for Alzheimer's Disease di-agnosis. Curr Alzheimer Res 2017; 14(11): 1149-54. [CrossRef] google scholar
2. 2. Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med 2012; 2(8): a006239. [CrossRef] google scholar
3. 3. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006; 63(2): 168-74. [CrossRef] google scholar
4. 4. Tanzi RE. The genetics of Alzheimer disease. Cold Spring Harb Per-spect Med 2012; 2(10): a006296. [CrossRef] google scholar
5. 5. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape ofAlzheimer disease: clinical implications and perspec-tives. Genet Med2016; 18(5): 421-30. [CrossRef] google scholar
6. 6. Nita M, Grzybowski A. The Role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. Oxid Med Cell Longev 2016; 2016: 3164734. [CrossRef] google scholar
7. 7. Tönnies E, Trushina E. Oxidative stress, synaptic dysfunction, and Alzheimer's Disease. J Alzheimers Dis 2017; 57(4): 1105-21. [Cross-Ref] google scholar
8. 8. Chen K, Kazachkov M, Yu PH. Effect of aldehydes derived from oxidative deamination and oxidative stress on 0-amyloid aggre-gation; pathological implications to Alzheimer's disease. J Neural Transm 2007; 114(6): 835-9. [CrossRef] google scholar

9. 9. Mayes J, Tinker-Mill C, Kolosov O, Zhang H, Tabner BJ, Allsop D. 0-Amyloid fibrils in Alzheimer Disease are not inert when bound to copper ions but can degrade hydrogen peroxide and gener-ate reactive oxygen species. J Biol Chem 2014; 289(17): 12052-62. [CrossRef] google scholar
10. 10. Aksenov MY, Tucker HM, Nair P, Aksenova MV, Butterfield DA, Es-tus S, et al. The expression of key oxidative stress-handling genes in different brain regions in Alzheimer's disease. J Mol Neurosci 1998; 11(2): 151-64. [CrossRef] google scholar
11. 11. Conrad M, Friedmann Angeli JP. Glutathione peroxidase 4 (Gpx4) and ferroptosis: what's so special about it? Mol Cell Oncol 2015; 2(3): e995047-e. [CrossRef] google scholar
12. 12. von Ossowski I, Hausner G, Loewen PC. Molecular evolutionary analysis based on the amino acid sequence of catalase. J Mol Evol 1993; 37(1): 71-6. [CrossRef] google scholar
13. 13. Habib LK, Lee MTC, Yang J. Inhibitors of catalase-amyloid inter-actions protect cells from beta-amyloid-induced oxidative stress and toxicity. J Biol Chem 2010; 285(50): 38933-43. [CrossRef] google scholar
14. 14. Liu X, Zhang Y, Zhuang L, Olszewski K, Gan B. NADPH debt drives redox bankruptcy: SLC7A11/xCT-mediated cystine uptake as a double-edge sword in cellular redox regulation. Genes & Diseases In press 2020. [CrossRef] google scholar
15. 15. Yan N, Zhang J-J. The Emerging roles of ferroptosis in vascular cognitive impairment. Front Neurosci 2019; 13(811). [CrossRef] google scholar
16. 16. Bowling AC, Beal MF. Bioenergetic and oxidative stress in neuro-degenerative diseases. Life Sci 1995; 56(14): 1151-71. [CrossRef] google scholar
17. 17. Ran Q, Gu M, Van Remmen H, Strong R, Roberts JL, Richardson A. Glutathione peroxidase 4 protects cortical neurons from oxida-tive injury and amyloid toxicity. J Neurosci Res 2006; 84(1): 202-8. [CrossRef] google scholar
18. 18. Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. Ablation of fer-roptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol 2017; 12: 8-17. [CrossRef] google scholar
19. 19. da Rocha TJ, Silva Alves M, Guisso CC, de Andrade FM, Camozzato A, de Oliveira AA, et al. Association of GPX1 and GPX4 polymor-phisms with episodic memory and Alzheimer's disease. Neurosci Lett 2018; 666: 32-7. [CrossRef] google scholar
20. 20. Bridges RJ, Natale NR, Patel SA. System xc- cystine/glutamate an-tiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 2012; 165(1): 20-34. [CrossRef] google scholar
21. 21. Qin S, Colin C, Hinners I, Gervais A, Cheret C, Mallat M. System Xc- and apolipoprotein E expressed by microglia have opposite effects on the neurotoxicity of amyloid-beta peptide 1-40. J Neu-rosci 2006; 26(12): 3345-56. [CrossRef] google scholar
22. 22. Lin C-H, Lin P-P, Lin C-Y, Lin C-H, Huang C-H, Huang Y-J, et al. De-creased mRNA expression for the two subunits of system xc-, SLC3A2 and SLC7A11, in WBC in patients with schizophrenia: Evi-dence in support of the hypo-glutamatergic hypothesis of schizo-phrenia. J Psychiatr Res 2016; 72: 58-63. [CrossRef] google scholar
23. 23. Nandi A, Yan L-J, Jana CK, Das N. Role of catalase in oxidative stress- and age-associated degenerative diseases. Oxid Med Cell Longev 2019; 2019: 9613090. [CrossRef] google scholar
24. 24. Gonzalez-Mundo I, Perez-Vielma NM, Gömez-Löpez M, Fleury A, Correa-Basurto J, Rosales-Hernandez MC, et al. DNA methyla-tion of the RE-1 silencing transcription factor in peripheral blood mononuclear cells and gene expression of antioxidant enzyme in patients with late-onset Alzheimer disease. Exp Gerontol 2020; 136: 110951. [CrossRef] google scholar
25. 25. Fernandez RF, Ellis JM. Acyl-CoA synthetases as regulators of brain phospholipid acyl-chain diversity. Prostaglandins Leukot Essent Fatty Acids 2020; 161: 102175. [CrossRef] google scholar
26. 26. Cho Y-Y. A novel role of brain-type ACS4 isotype in neuronal dif-ferentiation. Biochem Biophys Res Commun 2012; 419(3): 505-10. [CrossRef] google scholar
27. 27. Işıldak U, Somel M, Thornton JM, Dönertaş HM. Temporal changes in the gene expression heterogeneity during brain development and aging. Sci Rep 2020; 10(1): 4080. [CrossRef] google scholar
28. 28. Zheng Y, Ritzenthaler JD, Burke TJ, Otero J, Roman J, Watson WH. Age-dependent oxidation of extracellular cysteine/cystine redox state (Eh(Cys/CySS)) in mouse lung fibroblasts is mediated by a decline in Slc7a11 expression. Free Radic Biol Med 2018; 118: 1322. [CrossRef] google scholar
29. 29. Thiab NR, King N, McMillan M, Alghamdi OAS, Jones GL. Age-re-lated protein and mRNA expression of glutathione peroxidases (GPx) and Hsp-70 in different regions of rat kidney with and with-out stressor. AIMS Mol Sci 2016; 3(2): 125-37. [CrossRef] google scholar
30. 30. Tatone C, Carbone MC, Falone S, Aimola P, Giardinelli A, Caserta D, et al. Age-dependent changes in the expression of superoxide dismutases and catalase are associated with ultrastructural modi-fications in human granulosa cells. Mol Hum Reprod 2006; 12(11): 655-60. [CrossRef] google scholar