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Dimethyl Fumarate Mitigates Tauopathy in Aβ-Induced Neuroblastoma SH-SY5Y Cells

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Abstract

Alzheimer’s disease pathogenesis is measured by two key hallmarks viz extracellular senile plaques composed of insoluble amyloid beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau, resulting in microtubule destabilization, synaptic damage and neurodegeneration. Accumulation of Aβ is an introducing pathological incident in Alzheimer’s disease; hence, the effect of dimethyl fumarate (DMF) on Aβ1-42-induced alterations in phosphorylated tau, related protein kinases, fibrillogenesis and microtubule assembly in neuroblastoma SH-SY5Y cells was determined. DMF attenuated Aβ1-42-induced neuronal apoptosis by down-regulating protein levels of Bcl-2/Bax, cleaved caspase-3 and caspase-9. Aβ1-42-induced upsurge in tau phosphorylation at Ser396 and Thr231 epitopes was found to be declined by DMF pretreatment. The upregulated activity of glycogen synthase kinase-3 beta (GSK-3β) by Aβ1‑42 treatment was blocked by DMF pretreatment. PI3K substrate Akt (at Ser473) as well as Wnt dependent β-catenin and cyclin D1 activity was found to be upregulated by DMF pretreatment in Aβ1-42 treated cells. ThT fluorescence and MTT assay showed that DMF reduces Aβ fibrillogenesis and inhibit related cytotoxicity. Also, DMF exerts a protective effect on Aβ1-42-induced microtubule disassembly caused due to a reduction in polymerized β3-and α-tubulin. These results indicate that down-regulation of GSK-3β activity and subsequent activation of PI3K/Akt and Wnt/β-catenin signaling pathways are closely involved in the shielding effect of DMF against Aβ1-42-induced tau hyperphosphorylation. Modulating cellular events related to Aβ1-42-induced tau hyperphosphorylation, aggregation and microtubule stabilization offers new molecular insights into the defensive outcome of DMF towards appropriate management for Alzheimer’s disease.

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References

  1. Bloom GS (2014) Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71:505–508

    PubMed  Google Scholar 

  2. Mietelska-Porowska A, Wasik U, Goras M, Filipek A, Niewiadomska G (2014) Tau protein modifications and interactions: their role in function and dysfunction. Int J Mol Sci 15:4671–4713

    PubMed  PubMed Central  Google Scholar 

  3. Iqbal K, Liu F, Gong CX (2015) Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12:15–27

    PubMed  Google Scholar 

  4. Medina M, Garrido JJ, Wandosell FG (2011) Modulation of GSK-3 as a therapeutic strategy on tau pathologies. Front Mol Neurosci 4:24

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Pascoal TA, Mathotaarachchi S, Shin M et al (2017) Synergistic interaction between amyloid and tau predicts the progression to dementia. Alzheimer’s Dement 13:644–653

    Google Scholar 

  6. Rambaran RN, Serpell LC (2008) Amyloid fibrils: abnormal protein assembly. Prion 2:112–117

    PubMed  PubMed Central  Google Scholar 

  7. Krishtal J, Bragina O, Metsla K, Palumaa P, Tougu V (2017) In situ fibrillizing amyloid-beta1-42 induces neurite degeneration and apoptosis of differentiated SH-SY5Y cells. PLoS ONE 12:e0186636

    PubMed  PubMed Central  Google Scholar 

  8. Parihar MS, Brewer GJ (2010) Amyloid-β as a modulator of synaptic plasticity. J Alzheimer’s Dis 22:741–763

    CAS  Google Scholar 

  9. Mota SI, Ferreira IL, Pereira C, Oliveira CR, Rego AC (2012) Amyloid-beta peptide 1–42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures. Cur Alzheimer Res 9:844–856

    CAS  Google Scholar 

  10. Yaari R, Hake A (2015) Alzheimer’s disease clinical trials: past failures future opportunities. Clin Invest 5:297–309

    CAS  Google Scholar 

  11. Majkutewicz I, Kurowska E, Podlacha M et al (2018) Age-dependent effects of dimethyl fumarate on cognitive and neuropathological features in the streptozotocin-induced rat model of Alzheimer’s disease. Brain Res 1686:19–33

    CAS  PubMed  Google Scholar 

  12. Kappos L, Giovannoni G, Gold R et al (2015) Time course of clinical and neuroradiological effects of delayed-release dimethyl fumarate in multiple sclerosis. Eur J Neurol 22:664–671

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Campolo M, Casili G, Lanza M et al (2018) Multiple mechanisms of dimethyl fumarate in amyloid β-induced neurotoxicity in human neuronal cells. J Cell Mol Med 22:1081–1094

    CAS  PubMed  Google Scholar 

  14. Dahlgren KN, Manelli AM, Stine WB Jr et al (2002) Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 277:32046–32053

    CAS  PubMed  Google Scholar 

  15. Joshi HC, Cleveland DW (1989) Differential utilization of beta-tubulin isotypes in differentiating neurites. J Cell Biol 109:663–673

    CAS  PubMed  Google Scholar 

  16. Walker JM (1996) The bicinchoninic acid (BCA) assay for protein quantitation. In: Walker JM (ed) The protein protocols handbook. Springer protocols Handbooks. Humana Press, Totowa

    Google Scholar 

  17. Omar SH, Scott CJ, Hamlin AS, Obied HK (2019) Olive biophenols reduces Alzheimer’s pathology in SH-SY5Y cells and APPswe mice. Int J Mol Sci 20:125

    Google Scholar 

  18. Sun ZK, Yang HQ, Pan J et al (2008) Protective effects of erythropoietin on tau phosphorylation induced by β-amyloid. J Neurosci Res 86:3018–3027

    CAS  PubMed  Google Scholar 

  19. Cao M, Liu F, Ji F et al (2013) Effect of c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK) in morphine-induced tau protein hyperphosphorylation. Behav Brain Res 237:249–255

    CAS  PubMed  Google Scholar 

  20. Engel T, Hernandez F, Avila J, Lucas JJ (2006) Full reversal of Alzheimer's disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3. J Neurosci 26:5083–5090

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Li S, Jin M, Koeglsperger T et al (2011) Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B containing NMDA receptors. J Neurosci 31:6627–6638

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Eleanor D, Wisniewski T (2017) Alzheimer’s disease: experimental models and reality. Acta Neuropathol 133:155–175

    Google Scholar 

  23. Jang JH, Surh YJ (2004) Bcl-2 protects against Abeta (25–35)-induced oxidative PC12 cell death by potentiation of antioxidant capacity. Biochem Biophys Res Commun 320:880–886

    CAS  PubMed  Google Scholar 

  24. Wang C, Youle RJ (2009) The role of mitochondria in apoptosis. Annu Rev Genet 43:95–118

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yao M, Nguyen TV, Pike CJ (2005) Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. J Neurosci 25:1149–1158

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Du Q, Geller DA (2010) Cross-regulation between Wnt and NF-κB signaling pathways. Immunopathol Dis Therap 1:155–181

    Google Scholar 

  27. Du Y, Du Y, Zhang Y et al (2019) MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models. Sig Transduct Target Ther 4:58

    CAS  Google Scholar 

  28. Jin Y, Fan Y, Yan EZ (2006) Effects of sodium ferulate on amyloid-beta-induced MKK3/MKK6-p38 MAPK-Hsp27 signal pathway and apoptosis in rat hippocampus. Acta Pharmacol Sin 27:1309–1316

    CAS  PubMed  Google Scholar 

  29. Peng H, Guerau-de-Arellano M, Mehta VB et al (2012) Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor κB (NF-κB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 287:28017–28026

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Silva-Alvarez C, Arrazola MS, Godoy JA, Ordenes D, Inestrosa NC (2013) Canonical Wnt signaling protects hippocampal neurons from Aβ oligomers: role of non-canonical Wnt-5a/Ca(2+) in mitochondrial dynamics. Front Cell Neurosci 7:97

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Arrazola MS, Silva-Alvare C, Inestrosa NC (2015) How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario. Front Cell Neurosci 9:166

    PubMed  PubMed Central  Google Scholar 

  32. Kisoh K, Hayashi H, Itoh T et al (2017) Involvement of GSK-3β phosphorylation through PI3-K/Akt in cerebral ischemia-induced neurogenesis in rats. Mol Neurobiol 54:7917–7927

    CAS  PubMed  Google Scholar 

  33. Xian XF, Qing-Qiu M, Justin CY et al (2014) Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. J Alzheimer’s Dis 39:331–346

    CAS  Google Scholar 

  34. Toyama T, Looney AP, Baker BM et al (2018) Therapeutic targeting of TAZ and YAP by dimethyl fumarate in systemic sclerosis fibrosis. J Invest Dermatol 138:78–88

    CAS  PubMed  Google Scholar 

  35. Cuadrado A, Kugler S, Lastres-Becker I (2018) Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy. Redox Biol 14:522–534

    CAS  PubMed  Google Scholar 

  36. Henriques AG, Vieira SI, daCruz E et al (2010) Abeta promotes Alzheimer's disease-like cytoskeleton abnormalities with consequences to APP processing in neurons. J Neurochem 113:761–771

    CAS  PubMed  Google Scholar 

  37. Zabrecky JR, Cole RD (1982) Effect of ATP on the kinetics of microtubule assembly. J Biol Chem 257:4633–4638

    CAS  PubMed  Google Scholar 

  38. Marshall KE, Marchante R, Xue WF, Serpell LC (2014) The relationship between amyloid structure and cytotoxicity. Prion 8:192–196

    CAS  PubMed Central  Google Scholar 

  39. Wolfe LS, Calabrese MF, Nath A, Blaho DV, Miranker AD, Xiong Y (2010) Protein-induced photophysical changes to the amyloid indicator dye thioflavin T. PNAS USA 107:16863–16868

    CAS  PubMed  Google Scholar 

  40. Kees F (2013) Dimethyl fumarate: a Janus-faced substance? Expert Opin Pharmacother 14:1559–1567

    CAS  PubMed  Google Scholar 

  41. Demuro A, Parker I (2013) Cytotoxicity of intracellular Aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. J Neurosci 33:3824–3833

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Huang H, Taraboletti A, Shriver LP (2015) Dimethyl fumarate modulates antioxidant and lipid metabolism in oligodendrocytes. Redox Biol 5:169–175

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Herrmann AK, Wullner V, Moos S et al (2019) Dimethyl fumarate alters intracellular Ca2+ handling in immune cells by redox-mediated pleiotropic effects. Free Radic Biol Med 141:338–347

    CAS  PubMed  Google Scholar 

  44. Enache TA, Oliveira-Brett AM (2017) Alzheimer's disease amyloid beta peptides in vitro electrochemical oxidation. Bioelectrochemistry 114:13–23

    CAS  PubMed  Google Scholar 

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Acknowledgements

This research work was financially supported under SERB-National Postdoctoral Fellowship scheme, funded by Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India, New Delhi, India and the corresponding author is recipient of the Postdoctoral Fellowship (File No. PDF/2017/002802) from SERB, DST, India.

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Authors and Affiliations

  1. School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshashila Campus, Khandwa Road, Indore, M.P., 452001, India

    Mithun Singh Rajput, Devashish Rathore & Rashmi Dahima

  2. Institute of Nutrition, Mahidol University, 999 Phutthamonthon 4 Road, Salaya, 73170, Nakhon Pathom, Thailand

    Nilesh Prakash Nirmal

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  1. Mithun Singh Rajput
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  2. Nilesh Prakash Nirmal
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  3. Devashish Rathore
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  4. Rashmi Dahima
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Contributions

Conceptualization: MSR; Methodology: MSR, DR; Formal analysis and investigation: MSR, NPN; Writing—original draft preparation: MSR; Writing—review and editing: MSR, NPN, RD; Funding acquisition: MSR; Resources: MSR, DR, RD; Supervision: NPN, RD.

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Correspondence to Mithun Singh Rajput.

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Rajput, M.S., Nirmal, N.P., Rathore, D. et al. Dimethyl Fumarate Mitigates Tauopathy in Aβ-Induced Neuroblastoma SH-SY5Y Cells. Neurochem Res 45, 2641–2652 (2020). https://doi.org/10.1007/s11064-020-03115-x

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  • DOI: https://doi.org/10.1007/s11064-020-03115-x

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