The Effect of Fibroblast Growth Factor 21 on a Cellular Model of Alzheimer's Disease with Emphasis on Cell Viability and Mitochondrial Membrane Potential

Document Type : Research Paper

Authors

1 Iums,tehran, Iran

2 Shahed Univ.

3 Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran.

4 IUMS, Tehran, Iran

Abstract

Background and Objective: Alzheimer’s disease (AD) is a neurodegenerative disorder which is associated with extracellular accumulation of amyloid beta (Aβ) plaques. AD is accompanied by mitochondrial dysfunction and energy metabolism reduction. Fibroblast growth factor 21 (FGF21) is an endogenous polypeptide which its beneficial effects have been demonstrated on mitochondrial function, energy metabolism regulation and neuroprotection.
Materials and Methods: The present study was performed to investigate the effect of pretreatment with different concentrations of FGF21 [100,200 and 400 nM] on SH-SY5Y cells as a cellular model of AD induced by Ab(1-42). For induction of cellular model of AD. Ab(1-42) [20 µM] was added to SH-SY5Y cell medium. Cell viability (MTT assay) and mitochondrial membrane potential changes (Rhodamine 123 fluorescence intensity) were measured using microplate reader.
Results: The results of this study showed that Ab(1-42) enhances cell damage (p
Conclusion: Taken together, the results of this study suggest that FGF21 prevents cell death induced by Ab(1-42) in SH-SY5Y cells. It seems that the beneficial effects of FGF21 are mediated through mitochondrial membrane potential maintenance.

Keywords

References

1. Stuchbury G, Münch G. Alzheimer's associated inflammation, potential drug targets and future therapies. Journal of Neural Transmission 2005; 112(3):429-53.
2. Munch G, Schinzel R, Loske C, Wong A, Durany N, Li JJ, et al. Alzheimer’s disease-synergistic effects of glucose deficit, oxidative stress and advanced glycation end Products. Journal of Neural Transmission 1998; 105(4–5): 439–461.
3. Sato N, Morishita R. The roles of lipid and glucose metabolism in modulation of beta-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease. Frontiers in Aging Neuroscience 2015; 7: 199.
4. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, et al. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology 2010; 75(9): 764-70.
5. Roberts RO, Knopman DS, Przybelski SA, Mielke MM, Kantarci K, Preboske GM, et al. Association of type 2 diabetes with brain atrophy and cognitive impairment. Neurology 2014; 82(13): 1132-41.
6. Morris JK, Vidoni ED, Honea RA, Burns JM. Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiology of Aging 2014; 35(3): 585-9.
7. Heneka MT, Fink A, Doblhammer G. Effect of pioglitazone medication on the incidence of dementia. Annals of Neurology. 2105; 78(2):284-94.
8. Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 2013; 36(10):2981-7.
9. Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. The Journal of Biological Chemistry 2011; 286(15): 12983–12990.
10. Miguel Ángel Gómez-Sámano, Mariana Grajales-Gómez, Julia María Zuarth-Vázquez, Ma. Fernanda Navarro-Flores, Mayela Martínez-Saavedra, Óscar Alfredo Juárez-León, et al. Fibroblast growth factor 21 and its novel association with oxidative stress. Redox Biology 2017; 11: 335–341.
11. Lü Y, Liu JH, Zhang LK, DU J, Zeng XJ, Hao G, et al. Fibroblast growth factor 21 as a possible endogenous factor inhibits apoptosis in cardiac endothelial cells. Chinese Medical Journal (Engl.) 2010; 123(23): 3417–3421.
12. Schaap FG, Kremer AE, Lamers WH, Jansen PL, Gaemers IC. Fibroblast growth factor 21 is induced by endoplasmic reticulum stress. Biochimie 2013; 95(4): 692–699.
13. Cao SS, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxidants & Redox Signaling 2014; 21(3): 396–413.
14. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. The Journal of Clinical Investigation 2005; 115(6): 1627–1635.
15. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007; 148(2): 774–781.
16. Wente W, Efanov AM, Brenner M, Kharitonenkov A, Köster A, Sandusky GE, et al. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 2006; 55(9): 2470-8.
17. Kharitonenkov A, Shanafelt AB. FGF21: a novel prospect for the treatment of metabolic diseases. Current Opinion in Investigational Drugs 2009; 10(4): 359–364.
18. Itoh N, Ornitz DM. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. Journal of Diochemistry 2011; 149(2): 121–130.
19. Mäkelä J, Tselykh TV, Maiorana F, Eriksson O, Do HT, Mudò G, et al. Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1α in human dopaminergic neurons via Sirtuin-1. Springer Plus 2014; 3:1–12.
20. Liang Q, Zhong L, Zhang J, Wang Y, Bornstein SR, Triggle CR, et al. FGF21Maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 2014; 63(12): 4064–4075.
21. Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nature Medicine 2013; 19(9): 1147–115.
22. Kadowaki H, Nishitoh H, Urano F, Sadamitsu C, Matsuzawa A, Takeda K, et al. Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death and Differentiation 2005; 12(1):19–24.
23. Behl C. Hydrogen peroxide mediates amyloid β protein toxicity. Cell 1994; 77(6):817–827.
24. Chakrabarti S, Sinha M, Thakurta IG, Banerjee P, Chattopadhyay M. Oxidative stress and amyloid beta toxicity in Alzheimer’s disease: intervention in a complex relationship by antioxidants. Current Medicinal Chemistry 2013; 20(37): 4648–4664.
25. Shelat PB, Chalimoniuk M, Wang JH, Strosznajder JB, Lee JC, et al. Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cyto‌solic phospholipase A2 in cortical neurons. Journal of Neurochemistry 2008; 106(1): 45–55.
26. Hu H, Li M. Mitochondria-targeted antioxidant mitotempo protects mito-chondrial function against amyloid beta toxicity in primary cultured mouse neurons. Biochemical and Biophysical Research Communications 2016; 478(1): 174–180.
27. Qin L, Liu Y, Cooper C, Liu B, Wilson B, Hong J-S. Microglia enhance β- amyloid peptide-induced toxicity in cortical and mesen‌cephalic neurons by producing reactive oxygen species. Journal of Neurochemistry 2002; 83(4): 973–983.
28. Qin B, Cartier L, Dubois-dauphin M, Li B, Serrander L, Krause KH. A key role for the microglial NADPH oxidase in APP-dependent killing of neurons. Neurobiology of Aging 2006; 27(11): 1577–1587.
29. Estaquier J, Vallette F, Vayssiere JL, Mignotte B. The mitochondrial pathways of apoptosis. Advances in Experimental Medicine and Biology. 2012; 942: 157–83.
30. Joshi DC, Bakowska JC. Determination of mitochondrial membrane potential and reactive oxygen species in live rat cortical neurons. Journal of Visualized Experiments 2001; 51: 2704.
31. Kromer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis. Immunology Today 1997; 18(1): 44–51.
32. Russell CSJ, Lee WG. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophysical Journal 1999; 76(1 Pt 1):469-77.
33. Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y, Kimura M, et al. bKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Molecular Endocrinology 2008; 22(4): 1006–1014.
34. A. Suomalainen. Fibroblast growth factor 21: a novel biomarker for human muscle manifesting mitochondrial disorders. Expert Opinion on Medical Diagnostics 2013; 7(4): 313–317.
35. Vanhorebeek I, Ellger B, De Vos R, Boussemaere M, Debaveye Y, Perre SV, et al.Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness. Critical Care Medicine 2009; 37(4): 1355–1364.
36. Zhang C, Shao M, Yang H, Chen L, Yu L, Cong W, et al. Attenuation of hyperlipidemia- and diabetesinduced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal Inflammation. PLoS One 2013; 8(12): e82275.
37. Kim KH, Lee MS. FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs. Journal of Endocrinology 2015; 226(1): R1–R16.
38. Hsuchou H, Pan W, Kastin AJ. The fasting polypeptide FGF21 can enter brain from blood. Peptides 2007; 28(12): 2382–86.
39. Tan BK, Hallschmid M, Adya R, Kern W, Lehnert H,Randeva HS. Fibroblast growth factor 21 (FGF21) inhuman cerebrospinal fluid: relationship with plasmaFGF21 and body adiposity. Diabetes 2011; 60(11): 2758–62.
40. Mäkelä J, Tselykh TV, Maiorana F, Eriksson O, Do HT, Mudò G, et al. Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1α inhuman dopaminergic neurons via Sirtuin-1. Springerplus. 2014; 3:2.
41. Sa-Nguanmoo P, Chattipakorn N, Chattipakorn SC. Potential roles of fibroblast growth factor 21 in the brain. Metabolic Brain Disease 2016; 31(2): 239–48.
42. Leng Y, Wang Z, Tsai LK, Leeds P, Fessler EB, Wang J, et al. FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is dramatically elevated in neurons by mood stabilizers. Molecular Psychiatry 2015; 20(2): 215–223.
 

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