Volume 25, Issue 5 (9-2021)                   IBJ 2021, 25(5): 343-348 | Back to browse issues page

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Sedighi M, Baluchnejadmojarad T, Roghani M. Linagliptin Protects Human SH-SY5Y Neuroblastoma Cells against Amyloid-β Cytotoxicity via the Activation of Wnt1 and Suppression of IL-6 Release. IBJ. 2021; 25 (5) :343-348
URL: http://ibj.pasteur.ac.ir/article-1-3185-en.html
Background: Alzheimer’s disease is one of the neurodegenerative disorders typified by the aggregate of amyloid-β (Aβ) and phosphorylated tau protein. Oxidative stress and neuroinflammation, because of Aβ peptides, are strongly involved in the pathophysiology of Alzheimer’s disease (AD). Linagliptin shows neuroprotective properties against AD pathological processes through alleviation of neural inflammation and AMPK activation. Methods: We assessed the benefits of linagliptin pretreatment (at 10, 20, and 50 nM concentrations), against Aβ1-42 toxicity (20 μM) in SH-SY5Y cells. The concentrations of secreted cytokines, such as TNF-α, IL-6, and IL-1β, and signaling proteins, including pCREB, Wnt1, and PKCε, were quantified by ELISA. Results: We observed that Aβ led to cellular inflammation, which was assessed by measuring inflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, Aβ1-42 treatment impaired pCREB, PKCε, and Wnt1 signaling in human SH-SY5Y neuroblastoma cells. Addition of Linagliptin significantly reduced IL-6 levels in the lysates of cells, treated with Aβ1-42. Furthermore, linagliptin prevented the downregulation of Wnt1 in Aβ1-42-treated cells exposed. Conclusion: The current findings reveal that linagliptin alleviates Aβ1-42-induced inflammation in SH-SY5Y cells, probably through the suppression of IL-6 release, and some of its benefits are mediated through the activation of the Wnt1 signaling pathway.

1. Kumar A, Singh A. A review on Alzheimer's disease pathophysiology and its management. Pharmacological reports 2015; 67(2): 195-203. [DOI:10.1016/j.pharep.2014.09.004]
2. Dursun E, Gezen-Ak D, Hanağası H, Bilgiç B, Lohmann E, Ertan S, Atasoy İL, Alaylıoğlu M, Selin Araz Ö, Önal B, Gündüz A, Apaydın H, Kızıltan G, Ulutin T, Gürvit H, Yılmazer S. The interleukin1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease. Journal of neuroimmunology 2015; 283: 50-57. [DOI:10.1016/j.jneuroim.2015.04.014]
3. Liu L, Chan C. The role of inflammasome in Alzheimer's disease. Ageing research reviews 2014; 15: 6-15. [DOI:10.1016/j.arr.2013.12.007]
4. Sedighi M, Baluchnejadmojarad T, Fallah S, Moradi N, Afshin-Majd S, Roghani M. The association between circulating klotho and dipeptidyl peptidase-4 activity and inflammatory cytokines in elderly patients with Alzheimer disease. Basic and clinical neuroscience 2020; 11(3): 349-358 [DOI:10.32598/bcn.11.2.1747.1]
5. Das S, Basu A. Inflammation: a new candidate in modulating adult neurogenesis. Journal of neuroscience research 2008; 86(6): 1199-1208. [DOI:10.1002/jnr.21585]
6. Tapia-Rojas C, Inestrosa NC. Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20 APP transgenic and wild type mice. Journal of neurochemistry 2018; 144(4): 443-465. [DOI:10.1111/jnc.14278]
7. Ferrari DV, Avila ME, Medina MA, Pérez-Palma E, I Bustos B, A Alarcon M. Wnt/β-catenin signaling in Alzheimer's disease. CNS and neurological disorders drug targets 2014; 13(5): 745-754. [DOI:10.2174/1871527312666131223113900]
8. Forlenza OV, de Paula VJ, Machado-Vieira R, Diniz BS, Gattaz WF. Does lithium prevent Alzheimer's disease? Drugs and aging 2012; 29(5): 335-342. [DOI:10.2165/11599180-000000000-00000]
9. Parr C, Mirzaei N, Christian M, Sastre M. Activation of the Wnt/β-catenin pathway represses the transcription of the β-amyloid precursor protein cleaving enzyme (BACE1) via binding of T-cell factor-4 to BACE1 promoter. The FASEB journal 2015; 29(2): 623-635. [DOI:10.1096/fj.14-253211]
10. Yao Y, Chen X, Bao Y, Wu Y. Puerarin inhibits β- amyloid peptide 1-42-induced tau hyperphosphorylation via the Wnt/β-catenin signaling pathway. Molecular medicine reports 2017; 16(6): 9081-9085. [DOI:10.3892/mmr.2017.7702]
11. Sedighi M, Baluchnejadmojarad T, Fallah S, Moradi N, Afshin-Majdd S, Roghani M. Klotho ameliorates cellular inflammation via suppression of cytokine release and upregulation of mir-29a in the pbmcs of diagnosed Alzheimer's disease patients. Journal of molecular neuroscience 2019; 69(1): 157-165. [DOI:10.1007/s12031-019-01345-5]
12. Akita Y. Protein kinase C-ε (PKC-ε): its unique structure and function. The journal of biochemistry 2002; 132(6): 847-852. [DOI:10.1093/oxfordjournals.jbchem.a003296]
13. Lanni C, Mazzucchelli M, Porrello E, Govoni S, Racchi M. Differential involvement of protein kinase C alpha and epsilon in the regulated secretion of soluble amyloid precursor protein. European journal of biochemistry 2004; 271(14): 3068-3075. [DOI:10.1111/j.1432-1033.2004.04240.x]
14. Benito E, Barco A. CREB's control of intrinsic and synaptic plasticity. Trends in neurosciences 2010; 33(5): 230-240. [DOI:10.1016/j.tins.2010.02.001]
15. Pugazhenthi S, Wang M, Pham S, Sze CI, Eckman CB. Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons. Molecular neurodegeneration 2011; 6(1): 60. [DOI:10.1186/1750-1326-6-60]
16. Sedighi M, Baluchnejadmojarad T, Afshin-Majd S, Amiri M, Aminzade M, Roghani M. Anti-aging Klotho Protects SH-sy5y cells against amyloid β1-42 neurotoxicity: involvement of Wnt1/pCREB/Nrf2/HO-1 signaling. Journal of molecular neuroscience 2021; 71(1): 19-27. [DOI:10.1007/s12031-020-01621-9]
17. Amiri M, Braidy N, Aminzadeh M. Protective effects of fibroblast growth factor 21 against amyloid-beta1-42-induced toxicity in SH-SY5Y cells. Neurotoxicity research 2018; 34: 574-583. [DOI:10.1007/s12640-018-9914-2]
18. Filograna R, Civiero L, Ferrari V, Codolo G, Greggio E, Bubacco L, Beltramini M, Bisaglia M. Analysis of the catecholaminergic phenotype in human SH-SY5Y and BE(2)-M17 neuroblastoma cell lines upon differentiation. PLoS one 2015; 10(8): e0136769.
19. Yeo ETY, Wong KWL, See ML, Wong KY, Gan SY, Chan EWL. Piper sarmentosum Roxb. confers neuroprotection on beta-amyloid (Aβ)-induced microglia-mediated neuroinflammation and attenuates tau hyperphosphorylation in SH-SY5Y cells. Journal of ethnopharmacology 2018; 217: 187-194. [DOI:10.1016/j.jep.2018.02.025]
20. Kornelius E, Lin CL, Chang HH, Li HH, Huang WN, Yang YS, Lu YL, Peng CH, Huang CN. DPP-4 inhibitor linagliptin attenuates Aβ-induced cytotoxicity through activation of AMPK in neuronal cells. CNS neuroscience and therapeutics 2015; 21(7): 549-57. [DOI:10.1111/cns.12404]
21. Ni R, Kindler DR, Waag R, Rouault M, Ravikumar P, Nitsch R, Rudin M, Camici GG, Liberale L, Kulic L, Klohs J. FMRI reveals mitigation of cerebrovascular dysfunction by bradykinin receptors 1 and 2 inhibitor noscapine in a mouse model of cerebral amyloidosis. Frontiers in aging neuroscience 2019; 11:27. [DOI:10.3389/fnagi.2019.00027]
22. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Experimental neurology 2007; 208(1): 1-25. [DOI:10.1016/j.expneurol.2007.07.004]
23. Gupta P, Sil S, Ghosh R, Ghosh A, Ghosh T. Intracerebroventricular Aβ-induced neuroinflammation alters peripheral immune responses in rats. Journal of molecular neuroscience 2018; 66(4): 572-586. [DOI:10.1007/s12031-018-1189-9]
24. Gemma C, Bickford PC. Interleukin-1ß and Caspase-1: Players in the regulation of age-related cognitive dysfunction. Reviews in the neurosciences 2007; 18(2): 137-48. [DOI:10.1515/REVNEURO.2007.18.2.137]
25. Tian Y, Chen KY, Liu LD, Dong YX, Zhao P, Guo SB. Sevoflurane exacerbates cognitive impairment induced by Aβ1-40 in rats through initiating neurotoxicity, neuroinflammation, and neuronal apoptosis in rat hippocampus. Mediators of inflammation 2018; Article ID 3802324. [DOI:10.1155/2018/3802324]
26. Inestrosa NC, DeFerrari GV, Garrido JL, Alvarez A, Olivares GH, Barrı́a MaI, Marcelo achacon B. Wnt signaling involvement in β-amyloid-dependent neurodegeneration. Neurochemistry international 2002; 41(5): 341-344. [DOI:10.1016/S0197-0186(02)00056-6]
27. Vitolo OV, Sant'Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M. Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling. Proceedings of the national academy of sciences 2002; 99(20): 13217-13221. [DOI:10.1073/pnas.172504199]
28. Alkon DL, Sun M-K, Nelson TJ. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends in pharmacological sciences 2007; 28(2): 51-60. [DOI:10.1016/j.tips.2006.12.002]
29. Hölscher C. Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. CNS and neurological disorders drug targets 2012; 26(10): 871-882 [DOI:10.2165/11635890-000000000-00000]
30. Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a Novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. Journal of pharmacology and experimental therapeutics 2008; 325(1): 175-182. [DOI:10.1124/jpet.107.135723]
31. Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Annals of translational medicine 2015; 3(10): 136.
32. Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, Gerlo S. Interleukin-6, a mental cytokine. Brain research reviews 2011; 67(1-2): 157-183. [DOI:10.1016/j.brainresrev.2011.01.002]
33. Nakamura Y, Hasegawa H, Tsuji M, Oguchi T. Linagliptin inhibits lipopolysaccharide-stimulated interleukin-6 production, intranuclear p65 expression, and p38 mitogen-activated protein kinase phosphorylation in human umbilical vein endothelial cells. Renal replacement therapy 20196; 2(1): DOI: 10.1186/s41100-016-0030-6. [DOI:10.1186/s41100-016-0030-6]
34. Inestrosa NC, Varela-Nallar L. Wnt signaling in the nervous system and in Alzheimer's disease. Journal of molecular cell biology 2014; 6(1): 64-74. [DOI:10.1093/jmcb/mjt051]
35. Inestrosa NC, Varela-Nallar L. Wnt signalling in neuronal differentiation and development. Cell and tissue research 2015; 359(1): 215-223. [DOI:10.1007/s00441-014-1996-4]
36. De Strooper B, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nature reviews neurology 2010; 6(2): 99-107. [DOI:10.1038/nrneurol.2009.218]
37. Quintanilla RA, Muñoz FJ, Metcalfe MJ, Hitschfeld M, Olivares G, Godoy JA, Inestrosa NC. Trolox and 17 β-estradiol protect against amyloid β-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway. Journal of biological chemistry 2005; 280(12): 11615-11625. [DOI:10.1074/jbc.M411936200]
38. Gough S. Dipeptidyl peptidase-4 inhibitors. Handbook of Incretin-Based Therapies in Type 2 Diabetes. Switzerland: ADIS; 2016. [DOI:10.1007/978-3-319-08982-9]
39. Angelopoulou E, Piperi C. DPP-4 inhibitors: a promising therapeutic approach against Alzheimer's disease. Annals of translational medicine 2018; 6(12): 255. [DOI:10.21037/atm.2018.04.41]
40. Gault VA, Lennox R, Flatt PR. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline. Diabetes obesity and metabolism 2015; 17(4): 403-413. [DOI:10.1111/dom.12432]
41. DeFerrari G, Chacon M, Barria M, Garrido J, Godoy J, Olivares G, Reyes AE, Alvarez A, Bronfman M, Inestrosa NC. Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by β-amyloid fibrils. Molecular psychiatry 2003; 8(2): 195-208. [DOI:10.1038/sj.mp.4001208]

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