Cellular and Molecular Neurobiology

, Volume 37, Issue 2, pp 211–222 | Cite as

Reversal of Beta-Amyloid-Induced Neurotoxicity in PC12 Cells by Curcumin, the Important Role of ROS-Mediated Signaling and ERK Pathway

  • Cun-dong Fan
  • Yuan Li
  • Xiao-ting Fu
  • Qing-jian Wu
  • Ya-jun Hou
  • Ming-feng Yang
  • Jing-yi Sun
  • Xiao-yan FuEmail author
  • Zun-cheng ZhengEmail author
  • Bao-liang SunEmail author
Original Research


Progressive accumulation of beta-amyloid (Aβ) will form the senile plaques and cause oxidative damage and neuronal cell death, which was accepted as the major pathological mechanism to the Alzheimer’s disease (AD). Hence, inhibition of Aβ-induced oxidative damage and neuronal cell apoptosis by agents with potential antioxidant properties represents one of the most effective strategies in combating human AD. Curcumin (Cur) a natural extraction from curcuma longa has potential of pharmacological efficacy, including the benefit to antagonize Aβ-induced neurotoxicity. However, the molecular mechanism remains elusive. The present study evaluated the protective effect of Cur against Aβ-induced cytotoxicity and apoptosis in PC12 cells and investigated the underlying mechanism. The results showed that Cur markedly reduced Aβ-induced cytotoxicity by inhibition of mitochondria-mediated apoptosis through regulation of Bcl-2 family. The PARP cleavage, caspases activation, and ROS-mediated DNA damage induced by Aβ were all significantly blocked by Cur. Moreover, regulation of p38 MAPK and AKT pathways both contributed to this protective potency. Our findings suggested that Cur could effectively suppress Aβ-induced cytotoxicity and apoptosis by inhibition of ROS-mediated oxidative damage and regulation of ERK pathway, which validated its therapeutic potential in chemoprevention and chemotherapy of Aβ-induced neurotoxicity.


Beta-amyloid Curcumin Apoptosis Neurotoxicity Oxidative damage 



The study was supported by the National Natural Science Foundation of China Nos. 81471212 and 81271275 to B.-L. Sun and No. 81501106 to C.-D. Fan; the Natural Science Foundation of Shandong ZR2015HQ009 to C.-D. Fan, ZR2015PH003 to X.-Y. Fu and ZR2014HM046 to Z.-C. Zheng.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interest.

Supplementary material

10571_2016_362_MOESM1_ESM.doc (83 kb)
Supplementary material 1 (DOC 83 kb)


  1. Abe Y, Hashimoto S, Horie T (1999) Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res 39:41–47CrossRefPubMedGoogle Scholar
  2. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818CrossRefPubMedGoogle Scholar
  3. Boldt S, Weidle UH, Kolch W (2002) The role of MAPK pathways in the action of chemotherapeutic drugs. Carcinogenesis 23:1831–1838CrossRefPubMedGoogle Scholar
  4. Bonegio R, Lieberthal W (2002) Role of apoptosis in the pathogenesis of acute renal failure. Curr Opin Nephrol Hypertens 11:301–308CrossRefPubMedGoogle Scholar
  5. Boya P, Morales MC, Gonzalez-Polo RA, Andreau K, Gourdier I, Perfettini JL, Larochette N, Deniaud A, Baran-Marszak F, Fagard R, Feuillard J, Asumendi A, Raphael M, Pau B, Brenner C, Kroemer G (2003) The chemopreventive agent N-(4-hydroxyphenyl) retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family. Oncogene 22:6220–6230CrossRefPubMedGoogle Scholar
  6. Butterfield DA, Perluigi M, Sultana R (2006) Oxidative stress in Alzheimer’s disease brain: new insights from redox proteomics. Eur J Pharmacol 545:39–50CrossRefPubMedGoogle Scholar
  7. Chen T, Wong YS (2008) Selenocystine induces apoptosis of A375 human melanoma cells by activating ROS-mediated mitochondrial pathway and p53 phosphorylation. Cell Mol Life Sci 65:2763–2775CrossRefPubMedGoogle Scholar
  8. Chen T, Wong YS (2009) Selenocystine induces reactive oxygen species-mediated apoptosis in human cancer cells. Biomed Pharmacother 63:105–113CrossRefPubMedGoogle Scholar
  9. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403CrossRefPubMedGoogle Scholar
  10. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656CrossRefPubMedGoogle Scholar
  11. Czarna M, Jarmuszkiewicz W (2006) Role of mitochondria in reactive oxygen species generation and removal, relevance to signaling and programmed cell death. Postepy Biochem 52:145–156 PubMedGoogle Scholar
  12. Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD (2004) Free radicals and antioxidants in human health: current status and future prospects. J Assoc Physicians India 52:794–804PubMedGoogle Scholar
  13. Dickinson BC, Chang CJ (2011) Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat Chem Biol 7:504–511CrossRefPubMedPubMedCentralGoogle Scholar
  14. Eckert A, Schulz KL, Rhein V, Gotz J (2010) Convergence of amyloid-beta and tau pathologies on mitochondria in vivo. Mol Neurobiol 41:107–114CrossRefPubMedPubMedCentralGoogle Scholar
  15. Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G (2012) Curcumin—from molecule to biological function. Angew Chem Int Ed Engl 51:5308–5332CrossRefPubMedGoogle Scholar
  16. Fan C, Chen J, Wang Y, Wong YS, Zhang Y, Zheng W, Cao W, Chen T (2013) Selenocystine potentiates cancer cell apoptosis induced by 5-fluorouracil by triggering reactive oxygen species-mediated DNA damage and inactivation of the ERK pathway. Free Radic Biol Med 65:305–316CrossRefPubMedGoogle Scholar
  17. Festjens N, van Gurp M, van Loo G, Saelens X, Vandenabeele P (2004) Bcl-2 family members as sentinels of cellular integrity and role of mitochondrial intermembrane space proteins in apoptotic cell death. Acta Haematol 111:7–27CrossRefPubMedGoogle Scholar
  18. Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF (2006) Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res 81:47–63CrossRefPubMedGoogle Scholar
  19. Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA 73:2424–2428CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008) Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 65:1631–1652CrossRefPubMedPubMedCentralGoogle Scholar
  21. Henry-Mowatt J, Dive C, Martinou JC, James D (2004) Role of mitochondrial membrane permeabilization in apoptosis and cancer. Oncogene 23:2850–2860CrossRefPubMedGoogle Scholar
  22. Hilger RA, Scheulen ME, Strumberg D (2002) The Ras-Raf-MEK-ERK pathway in the treatment of cancer. Onkologie 25:511–5118PubMedGoogle Scholar
  23. Ho YS, Vincent R, Dey MS, Slot JW, Crapo JD (1998) Transgenic models for the study of lung antioxidant defense: enhanced manganese-containing superoxide dismutase activity gives partial protection to B6C3 hybrid mice exposed to hyperoxia. Am J Respir Cell Mol Biol 18:538–547CrossRefPubMedGoogle Scholar
  24. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223CrossRefPubMedGoogle Scholar
  25. Huang HC, Jiang ZF (2009) Accumulated amyloid-beta peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer’s disease. J Alzheimers Dis 16:15–27PubMedGoogle Scholar
  26. Isabelle M, Moreel X, Gagné JP, Rouleau M, Ethier C, Gagné P, Hendzel MJ, Poirier GG (2010) Investigation of PARP-1, PARP-2, and PARG interactomes by affinity-purification mass spectrometry. Proteome Sci. doi: 10.1186/1477-5956-8-22 PubMedPubMedCentralGoogle Scholar
  27. Jo SK, Cho WY, Sung SA, Kim HK, Won NH (2005) MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis. Kidney Int 67:458–466CrossRefPubMedGoogle Scholar
  28. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489CrossRefPubMedGoogle Scholar
  29. Lloyd DR, Phillips DH, Carmichael PL (1997) Generation of putative intrastrand cross-links and strand breaks in DNA by transition metal ion-mediated oxygen radical attack. Chem Res Toxicol 10:393–400CrossRefPubMedGoogle Scholar
  30. Maier HM, Ilich JZ, Kim JS, Spicer MT (2013) Nutrition supplementation for diabetic wound healing: a systematic review of current literature. Skinmed 11:217–224 quiz 224–245 PubMedGoogle Scholar
  31. Manolova Y, Deneva V, Antonov L, Drakalska E, Momekova D, Lambov N (2014) The effect of the water on the curcumin tautomerism: a quantitative approach. Spectrochim Acta A Mol Biomol Spectrosc 132:815–820CrossRefPubMedGoogle Scholar
  32. Meng J, Li Y, Camarillo C, Yao Y, Zhang Y, Xu C, Jiang L (2014) The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity. PLoS ONE 9:e85570CrossRefPubMedPubMedCentralGoogle Scholar
  33. Miranda S, Opazo C, Larrondo LF, Munoz FJ, Ruiz F, Leighton F, Inestrosa NC (2000) The role of oxidative stress in the toxicity induced by amyloid beta-peptide in Alzheimer’s disease. Prog Neurobiol 62:633–648CrossRefPubMedGoogle Scholar
  34. Nagata S (1997) Apoptosis by death factor. Cell 88:355–365CrossRefPubMedGoogle Scholar
  35. Onyango IG, Khan SM (2006) Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer’s disease. Curr Alzheimer Res 3:339–349CrossRefPubMedGoogle Scholar
  36. Pagani L, Eckert A (2011) Amyloid-Beta interaction with mitochondria. Int J Alzheimers Dis. doi: 10.4061/2011/925050 PubMedPubMedCentralGoogle Scholar
  37. Park SY, Kim HS, Cho EK, Kwon BY, Phark S, Hwang KW, Sul D (2008) Curcumin protected PC12 cells against beta-amyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Food Chem Toxicol 46:2881–2887CrossRefPubMedGoogle Scholar
  38. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183PubMedGoogle Scholar
  39. Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (2003) The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 66:1499–1503CrossRefPubMedGoogle Scholar
  40. Rada B, Leto TL (2008) Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol 15:164–187CrossRefPubMedPubMedCentralGoogle Scholar
  41. Rao PP, Mohamed T, Teckwani K, Tin G (2015) Curcumin binding to beta amyloid: a computational study. Chem Biol Drug Des 86:813–820CrossRefPubMedGoogle Scholar
  42. Riviere C, Richard T, Quentin L, Krisa S, Merillon JM, Monti JP (2007) Inhibitory activity of stilbenes on Alzheimer’s beta-amyloid fibrils in vitro. Bioorg Med Chem 15:1160–1167CrossRefPubMedGoogle Scholar
  43. Salvesen GS (2002) Caspases: opening the boxes and interpreting the arrows. Cell Death Differ 9:3–5CrossRefPubMedGoogle Scholar
  44. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39–85CrossRefPubMedGoogle Scholar
  45. Selkoe DJ (1997) Alzheimer’s disease: genotypes, phenotypes, and treatments. Science 275:630–631CrossRefPubMedGoogle Scholar
  46. Selkoe DJ (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 8:447–453CrossRefPubMedGoogle Scholar
  47. Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X (2012) Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J Neurochem 120:419–429CrossRefPubMedGoogle Scholar
  48. Swerdlow RH (2007) Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies. J Neurosci Res 85:3416–3428CrossRefPubMedGoogle Scholar
  49. van Gurp M, Festjens N, van Loo G, Saelens X, Vandenabeele P (2003) Mitochondrial intermembrane proteins in cell death. Biochem Biophys Res Commun 304:487–497CrossRefPubMedGoogle Scholar
  50. Zhao LN, Chiu SW, Benoit J, Chew LY, Mu Y (2012) The effect of curcumin on the stability of Abeta dimers. J Phys Chem B 116:7428–7435CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Key Lab of Cerebral Microcirculation in Universities of ShandongTaishan Medical UniversityTaianChina
  2. 2.School of Basic MedicineTaishan Medical UniversityTaianChina
  3. 3.Departments of RehabilitationTaian Central HospitalTaianChina

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