Neurochemical Research

, Volume 42, Issue 2, pp 468–480 | Cite as

Epigallocatechin Gallate Attenuates β-Amyloid Generation and Oxidative Stress Involvement of PPARγ in N2a/APP695 Cells

Original Paper


The accumulation of β-amyloid (Aβ) peptide plaques is a major pathogenic event in Alzheimer’s disease (AD). Aβ is a cleaved fragment of APP via BACE1, which is the rate-limiting enzyme in APP processing and Aβ generation. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered to be a potential target for AD treatment, because of its potent antioxidant and inhibitory effects on Aβ production by negatively regulating BACE1. Epigallocatechin gallate (EGCG), a highly active catechin found in green tea, is known to enhance metabolic activity and cognitive ability in the mice model of AD. To investigate whether the therapeutic effect of EGCG is related to the PPARγ pathway, we analysed the alterations in the intracellular molecular expression of PPARγ after EGCG treatment in the N2a/APP695 cell line. In this study, we observed that EGCG attenuated Aβ generation in N2a/APP695 cells, such as the PPARγ agonist, pioglitazone, by suppressing the transcription and translation of BACE1 and that its effect was attenuated by the PPARγ inhibitor, GW9662. Intriguingly, EGCG significantly reinforced the activity of PPARγ by promoting its mRNA and protein expressions in N2a/APP695 cells. Moreover, EGCG also decreased the expression of pro-apoptotic proteins (Bax, caspase-3), reduced the activity of the anti-inflammatory agent NF-κB and inhibited the oxidative stress by decreasing the levels of ROS and MDA and increasing the expression of MnSOD. Co-administration of GW9662 also significantly decreased the EGCG-mediated neuroprotective effect evidenced by the increase in oxidative stress and inflammatory markers. The therapeutic efficacy of EGCG in AD may be derived from the up-regulation of PPARγ mRNA and protein expressions.


Alzheimer’s disease (AD) Epigallocatechin gallate (EGCG) β-Amyloid PPARγ BACE1 



Alzheimer’s disease

β-Amyloid peptides


Amyloid precursor protein


β-Site amyloid precursor protein-cleaving enzyme 1


Peroxisome proliferator activated receptor-γ





This work was supported by Grants from the National Natural Science Foundation of China (No. 81303013).


  1. 1.
    Song MS, Rauw G, Baker GB, Kar S (2008) Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation. Eur J Neurosci 28:1989–2002CrossRefPubMedGoogle Scholar
  2. 2.
    Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418:291CrossRefPubMedGoogle Scholar
  3. 3.
    Wang X, Wang Y, Hu JP, Yu S, Li BK, Cui Y et al (2016) Astragaloside IV, a natural PPARgamma agonist, reduces abeta production in Alzheimer’s disease through inhibition of BACE1. Mol Neurobiol. doi: 10.1007/s12035-016-9874-6
  4. 4.
    Zhou W, Cai F, Li Y, Yang GS, O’Connor KD, Holt RA et al (2010) BACE1 gene promoter single-nucleotide polymorphisms in Alzheimer’s disease. J Mol Neurosci 42:127–133CrossRefPubMedGoogle Scholar
  5. 5.
    Zheng K, Dai X, Xiao N, Wu X, Wei Z, Fang W et al (2016) Curcumin ameliorates memory decline via inhibiting bace1 expression and beta-amyloid pathology in 5×FAD transgenic mice. Mol Neurobiol. doi: 10.1007/s12035-016-9802-9
  6. 6.
    Zhao Y, Wang Y, Hu J, Zhang X, Zhang YW (2012) CutA divalent cation tolerance homolog (Escherichia coli) (CUTA) regulates beta-cleavage of beta-amyloid precursor protein (APP) through interacting with beta-site APP cleaving protein 1 (BACE1). J Biol Chem 287:11141–11150CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712CrossRefPubMedGoogle Scholar
  8. 8.
    Guo LL, Guan ZZ, Huang Y, Wang YL, Shi JS (2013) The neurotoxicity of beta-amyloid peptide toward rat brain is associated with enhanced oxidative stress, inflammation and apoptosis, all of which can be attenuated by scutellarin. Exp Toxicol Pathol 65:579–584CrossRefPubMedGoogle Scholar
  9. 9.
    Cai Z, Zhao B, Ratka A (2011) Oxidative stress and beta-amyloid protein in Alzheimer’s disease. Neuromolecular Med 13:223–250CrossRefPubMedGoogle Scholar
  10. 10.
    Chen Z, Zhong C (2014) Oxidative stress in Alzheimer’s disease. Neurosci Bull 30:271–281CrossRefPubMedGoogle Scholar
  11. 11.
    Schwalm MT, Pasquali M, Miguel SP, Dos Santos JP, Vuolo F, Comim CM et al (2014) Acute brain inflammation and oxidative damage are related to long-term cognitive deficits and markers of neurodegeneration in sepsis-survivor rats. Mol Neurobiol 49:380–385CrossRefPubMedGoogle Scholar
  12. 12.
    Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M et al (2012) Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int J Neuropsychopharmacol 15:77–90CrossRefPubMedGoogle Scholar
  13. 13.
    Lin N, Chen LM, Pan XD, Zhu YG, Zhang J, Shi YQ et al (2015) Tripchlorolide attenuates beta-amyloid generation via suppressing PPARgamma-regulated BACE1 activity in N2a/APP695 Cells. Mol Neurobiol 53:6397–6406Google Scholar
  14. 14.
    Barroso E, del Valle J, Porquet D, Vieira Santos AM, Salvado L, Rodriguez-Rodriguez R et al (2013) Tau hyperphosphorylation and increased BACE1 and RAGE levels in the cortex of PPARbeta/delta-null mice. Biochim Biophys Acta 1832:1241–1248CrossRefPubMedGoogle Scholar
  15. 15.
    Abdallah DM (2010) Anticonvulsant potential of the peroxisome proliferator-activated receptor gamma agonist pioglitazone in pentylenetetrazole-induced acute seizures and kindling in mice. Brain Res 1351:246–253CrossRefPubMedGoogle Scholar
  16. 16.
    Nicolakakis N, Hamel E (2010) The nuclear receptor PPARgamma as a therapeutic target for cerebrovascular and brain dysfunction in Alzheimer’s disease. Front Aging Neurosci 2. doi: 10.3389/fnagi.2010.00021
  17. 17.
    Rani N, Bharti S, Bhatia J, Nag TC, Ray R, Arya DS (2016) Chrysin, a PPAR-gamma agonist improves myocardial injury in diabetic rats through inhibiting AGE-RAGE mediated oxidative stress and inflammation. Chem Biol Interact 250:59–67CrossRefPubMedGoogle Scholar
  18. 18.
    Quan Q, Wang J, Li X, Wang Y (2013) Ginsenoside Rg1 decreases Abeta(1–42) level by upregulating PPARgamma and IDE expression in the hippocampus of a rat model of Alzheimer’s disease. PLoS One 8:e59155CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG et al (2008) Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and Abeta production. Neurobiol Dis 29:422–437CrossRefPubMedGoogle Scholar
  20. 20.
    Kaundal RK, Sharma SS (2010) Peroxisome proliferator-activated receptor gamma agonists as neuroprotective agents. Drug News Perspect 23:241–256CrossRefPubMedGoogle Scholar
  21. 21.
    Jiang M, Jerome WG, Hayward SW (2010) Autophagy in nuclear receptor PPARgamma-deficient mouse prostatic carcinogenesis. Autophagy 6:175–176CrossRefPubMedGoogle Scholar
  22. 22.
    Nenov MN, Laezza F, Haidacher SJ, Zhao Y, Sadygov RG, Starkey JM et al (2014) Cognitive enhancing treatment with a PPARgamma agonist normalizes dentate granule cell presynaptic function in Tg2576 APP mice. J Neurosci 34:1028–1036CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Xicota L, Rodriguez-Morato J, Dierssen M, de la Torre R (2015) Potential role of (–)-epigallocatechin-3-gallate (EGCG) in the secondary prevention of Alzheimer disease. Curr Drug Targets 29:665–672Google Scholar
  24. 24.
    He Y, Cui J, Lee JC, Ding S, Chalimoniuk M, Simonyi A et al (2011) Prolonged exposure of cortical neurons to oligomeric amyloid-beta impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (–)-epigallocatechin-3-gallate. ASN Neuro 3:e00050PubMedPubMedCentralGoogle Scholar
  25. 25.
    Gao Z, Han Y, Hu Y, Wu X, Wang Y, Zhang X et al (2016) Targeting HO-1 by epigallocatechin-3-gallate reduces contrast-induced renal injury via anti-oxidative stress and anti-inflammation pathways. PLoS One 11:e0149032CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhang S, Yang X, Luo J, Ge X, Sun W, Zhu H et al (2014) PPARalpha activation sensitizes cancer cells to epigallocatechin-3-gallate (EGCG) treatment via suppressing heme oxygenase-1. Nutr Cancer 66:315–324CrossRefPubMedGoogle Scholar
  27. 27.
    Dragicevic N, Smith A, Lin X, Yuan F, Copes N, Delic V et al (2011) Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer’s amyloid-induced mitochondrial dysfunction. J Alzheimers Dis 26:507–521PubMedGoogle Scholar
  28. 28.
    El-Sahar AE, Safar MM, Zaki HF, Attia AS, Ain-Shoka AA (2015) Neuroprotective effects of pioglitazone against transient cerebral ischemic reperfusion injury in diabetic rats: modulation of antioxidant, anti-inflammatory, and anti-apoptotic biomarkers. Pharmacol Rep 67:901–906CrossRefPubMedGoogle Scholar
  29. 29.
    Mao JW, Tang HY, Wang YD (2012) Influence of rosiglitazone on the expression of PPARgamma, NF-kappaB, and TNF-alpha in rat model of ulcerative colitis. Gastroenterol Res Pract 2012:845672CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhang X, Wu M, Lu F, Luo N, He ZP, Yang H (2014) Involvement of alpha7 nAChR signaling cascade in epigallocatechin gallate suppression of beta-amyloid-induced apoptotic cortical neuronal insults. Mol Neurobiol 49:66–77CrossRefPubMedGoogle Scholar
  31. 31.
    Sun TL, Liu Z, Qi ZJ, Huang YP, Gao XQ, Zhang YY (2016) (–)-Epigallocatechin-3-gallate (EGCG) attenuates arsenic-induced cardiotoxicity in rats. Food Chem Toxicol 93:102–110CrossRefPubMedGoogle Scholar
  32. 32.
    Jang S, Jeong HS, Park JS, Kim YS, Jin CY, Seol MB et al (2010) Neuroprotective effects of (–)-epigallocatechin-3-gallate against quinolinic acid-induced excitotoxicity via PI3K pathway and NO inhibition. Brain Res 1313:25–33CrossRefPubMedGoogle Scholar
  33. 33.
    Karmakar I, Haldar S, Chakraborty M, Chaudhury K, Dewanjee S, Haldar PK (2016) Regulation of apoptosis through bcl-2/bax proteins expression and DNA damage by Zanthoxylum alatum. Pharm Biol 54:503–508CrossRefPubMedGoogle Scholar
  34. 34.
    Golde TE (2005) The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol 15:84–87CrossRefPubMedGoogle Scholar
  35. 35.
    Kowalska A (2004) The beta-amyloid cascade hypothesis: a sequence of events leading to neurodegeneration in Alzheimer’s disease. Neurol Neurochir Pol 38:405–411PubMedGoogle Scholar
  36. 36.
    Gao R, Wang Y, Pan Q, Huang G, Li N, Mou J et al (2015) Fuzhisan, a chinese herbal medicine, suppresses beta-secretase gene transcription via upregulation of SIRT1 expression in N2a-APP695 cells. Int J Clin Exp Med 8:7231–7240PubMedPubMedCentralGoogle Scholar
  37. 37.
    Hitt B, Riordan SM, Kukreja L, Eimer WA, Rajapaksha TW, Vassar R (2012) beta-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J Biol Chem 287:38408–38425CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wong PC (2008) Translational control of BACE1 may go awry in Alzheimer’s disease. Neuron 60:941–943CrossRefPubMedGoogle Scholar
  39. 39.
    Shimmyo Y, Kihara T, Akaike A, Niidome T, Sugimoto H (2008) Epigallocatechin-3-gallate and curcumin suppress amyloid beta-induced beta-site APP cleaving enzyme-1 upregulation. Neuroreport 19:1329–1333CrossRefPubMedGoogle Scholar
  40. 40.
    Wang R, Chen S, Liu Y, Diao S, Xue Y, You X et al (2015) All-trans-retinoic acid reduces BACE1 expression under inflammatory conditions via modulation of nuclear factor kappaB (NFkappaB) signaling. J Biol Chem 290:22532–22542CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Zheng N, Yuan P, Li C, Wu J, Huang J (2015) Luteolin reduces BACE1 expression through NF-kappaB and through estrogen receptor mediated pathways in HEK293 and SH-SY5Y cells. J Alzheimers Dis 45:659–671PubMedGoogle Scholar
  42. 42.
    Wang R, Li JJ, Diao S, Kwak YD, Liu L, Zhi L et al (2013) Metabolic stress modulates Alzheimer’s beta-secretase gene transcription via SIRT1-PPARgamma-PGC-1 in neurons. Cell Metab 17:685–694CrossRefPubMedGoogle Scholar
  43. 43.
    Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C et al (2005) Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128:1442–1453CrossRefPubMedGoogle Scholar
  44. 44.
    Jiang LY, Tang SS, Wang XY, Liu LP, Long Y, Hu M et al (2012) PPARgamma agonist pioglitazone reverses memory impairment and biochemical changes in a mouse model of type 2 diabetes mellitus. CNS Neurosci Ther 18:659–666CrossRefPubMedGoogle Scholar
  45. 45.
    Liu LP, Yan TH, Jiang LY, Hu W, Hu M, Wang C et al (2013) Pioglitazone ameliorates memory deficits in streptozotocin-induced diabetic mice by reducing brain beta-amyloid through PPARgamma activation. Acta Pharmacol Sin 34:455–463CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Wang F, Liu Y, Bi Z (2016) Pioglitazone inhibits growth of human retinoblastoma cells via regulation of NF-kappaB inflammation signals. J Recept Signal Transduct Res 1:1–6Google Scholar
  47. 47.
    Valles SL, Dolz-Gaiton P, Gambini J, Borras C, Lloret A, Pallardo FV et al (2010) Estradiol or genistein prevent Alzheimer’s disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes. Brain Res 1312:138–144CrossRefPubMedGoogle Scholar
  48. 48.
    Kalinin S, Richardson JC, Feinstein DL (2009) A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res 6:431–437CrossRefPubMedGoogle Scholar
  49. 49.
    Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V et al (2005) A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437:759–763CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Lee JY, Paik JS, Yun M, Lee SB, Yang SW (2016) The effect of (–)-epigallocatechin-3-gallate on il-1beta induced il-8 expression in orbital fibroblast from patients with thyroid-associated ophthalmopathy. PLoS One 11:e0148645CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA et al (2015) Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother 74:101–110CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of NeurologyThe Shandong Province Qianfoshan HospitalJinanChina
  2. 2.Division of Medical Quality ControlThe Shandong Province Qianfoshan HospitalJinanChina

Personalised recommendations