Curcumin inhibits APOE4-induced injury by activating peroxisome proliferator-activated receptor-γ (PPARγ) in SH-SY5Y cells

Document Type : Original Article


1 Pharmaceutical Institute, Pharmaceutical College of Henan University, Kaifeng 475004, China

2 Agricultural College of Inner Mongolia University for Nationalities, Tongliao, 028043, China


Objective(s): The human apolipoprotein E4 (APOE4) is associated with various brain injuries and neurodegenerative changes. Curcumin is an active ingredient isolated from the root of turmeric and is believed to have therapeutic effects on neurodegenerative diseases. The aim of this study was to investigate the effects of curcumin on APOE4-induced neurological damage and explore its molecular mechanisms.
Materials and Methods: SH-SY5Y cells were pretreated with curcumin for 24 hr and transfected with human APOE4 gene using Lipofectamine 2000. Then, the effect of curcumin on the transfected cells was detected by ELISA, immunofluorescence staining and Western blot.
Results: The production or expression of proinflammatory cytokines and proteins, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was significantly increased in SH-SY5Y cells transfected with APOE4, and curcumin inhibited APOE4-induced cellular inflammatory damage. Western blot analysis showed that, after transfection with APOE4, the expression of total nuclear factor kappa B (NF-κB) p65 and p-NF-κB p65 in the nucleus was increased, and curcumin inhibited the nuclear translocation of p65. The overexpression of APOE4 inhibited the expression of peroxisome proliferator-activated receptor-γ (PPARγ), whereas curcumin reversed and increased the expression of PPARγ protein. Down-regulating PPAR-γ with the inhibitor GW9662 and the shPPARγ gene confirmed that the NF-κB signaling pathway was inhibited by PPARγ.
Conclusion: This study suggests that APOE4 overexpression can induce cellular inflammatory damage, and pretreatment of curcumin could exert an anti-inflammatory effect by upregulating the expression of PPARγ to inhibit the activation of NF-κB signaling pathway.


1. Kurosinski P, Guggisberg M, Jurgen G. Alzheimer’s and Parkinson’s disease--overlapping or synergistic pathologies. Trends Mol Med 2002; 8:3-5.
2. Mattson MP, Pedersen WA, Duan W, Culmsee C, Camandola S. Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer’s and Parkinson’s diseases. Ann N Y Acad Sci 2010; 893:154-175.
3. Zhu S, Wang J, Zhang Y, He J, Kong J, Wang J, et al. The role of neuro-inflammation and amyloid in cognitive impairment in an APP/PS1 transgenic mouse model of Alzheimer’s disease. CNS Neurosci Ther 2017; 23:310-320.
4. Sprenkle NT, Sims SG, Cristina L, Sánchez CL, Meares GP. Endoplasmic reticulum stress and inflammation in the central nervous system. Mol Neurodegener 2017; 12:42-60.
5. Noh Y, Seo SW, Jeon S, Lee J, Kim J, Kim GH, et al. White matter hyperintensities are associated with amyloid burden in APOE4 non-carriers. J Alzheimers Dis 2014; 40:877-886.
6. Kantarci K, Lowe V, Przybelski SA, Weigand SD, Senjem ML, Ivnik RJ, et al. APOE modifies the association between Aβ load and cognition in cognitively normal older adults. Neurology 2012; 78:232-240.
7. Liraz OA, Boehm-Cagan A, Michaelson DM. ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice. Mol Neurodegener 2013; 8:16-33.
8. Lynch JR, Tang W, Wang H, Vitek MP, Bennett E, Sullivan P, et al. APOE genotype and an apoe-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem 2003; 278:48529-48533.
9. Yang Y, Cudaback E, Jorstad NL, Hemingway J, Hagan CE, Melief EJ, et al. APOE3, but not APOE4, bone marrow transplantation mitigates behavioral and pathological changes in a mouse model of Alzheimer disease. Am J Pathol 2013; 183:905-917.
10. Rodriguez GA, Tai LM, Ladu MJ, Rebeck GW. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflammation 2014; 11:111-144.
11. Yuen CY, Wong W, Tian XY, Wong SL, Lau CW, Yu J, et al. Telmisartan inhibits vasoconstriction via PPARγ-dependent expression and activation of endothelial nitric oxide synthase. Cardiovasc Res 2011; 90:122-129.
12. Yuen CY, Wong W, Tian XY, Wong SL, Lau C W, Yu J, et al. Chrysophanol demonstrates anti-inflammatory properties in LPS-primed RAW 264.7 macrophages through activating PPAR-γ. Int Immunopharmacol 2018; 56:90-97.
13. Miriyala S, Panchatcharam M, Rengarajulu P. Cardioprotective effects of curcumin. Adv Exp Med Biol 2007; 595:359-377.
14. Lee W, Loo C, Bebawy M, Luk F, Mason RS, Rohanizadeh R. Curcumin and its derivatives: Their application in neuropharmacology and neuroscience in the 21st century. Curr Neuropharmacol 2013; 11:338-378.
15. Ganguli M, Chandra V, Kamboh MI, Johnston JM, Dodge HH, Thelma BK, et al. Apolipoprotein E polymorphism and Alzheimer disease: The indo-US cross-national dementia study. Arch Neurol 2000; 57:824-830.
16. Potter PE. Curcumin: a natural substance with potential efficacy in Alzheimer’s disease. J Exp Pharmacol 2013; 5:23-31.
17. Gupta SC, Patchva S, Koh W, Aggarwal BB. Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol 2012; 39:283-299.
18. Reddy AC, Lokesh BR. Studies on spice principles as antioxidants in the inhibition of lipid peroxidation of rat liver microsomes. Mol Cell Biochem 1992; 111:117-124.
19. Adiwidjaja J, Mclachlan AJ, Boddy AV. Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions. Expert Opin Drug Metab Toxicol 2017; 13:953-972.
20. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: A component of tumeric. J Altern Complement Med 2003; 9:161-168.
21. Chen M, Li K, Li H, Song C, Miao Y. The glutathione peroxidase gene family in gossypium hirsutum: genome-wide identification, classification, gene expression and functional analysis. Sci Rep 2017; 7:44743-447458.
22. Cheng X, Li M, Du J, Jiang QY, Wang L, Yan SY, et al. Neuronal apoptosis in the developing cerebellum. Anat Histol Embryol 2011; 40:21-27.
23. Xi Y, Chen WJ, Deng JX, Cui ZJ, Liu HL, Yan MC, et al. Vasculature-guided neural migration in mouse cerebellum. Ital J Zool 2015; 82:15-24.
24. Guo Z, Lin J, Chang L, Xu Z, Cai X. Features of cardiomyocyte division during rat heart development. Pak J zool 2011; 43:321-330.
25. Yan M, Wang X, Deng J, Wang L, Cui Z, Shi Z. DNA methylation and cerebellar development, the regulation of Notch and Shh pathway. Ital J Zool 2016; 83:1-9.
26. Mailleux J, Timmermans S, Nelissen K, Vanmol J, Vanmierlo T, Van Horssen J, et al. Low-density lipoprotein receptor deficiency attenuates neuro-inflammation through the induction of apolipoprotein E. Front Immunol 2017; 8:1701-1701.
27. Sanan DA, Weisgraber KH, Russell SJ, Mahley R W, Huang D, Saunders AM, et al. Apolipoprotein E associates with beta amyloid peptide of Alzheimer’s disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 1994; 94:860-869.
28. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261:921-923.
29. Liu C, Zhao N, Fu Y, Wang N, Linares C, Tsai CW, et al. Apoe4 accelerates early seeding of amyloid pathology. Neuron 2017; 96:1024-1032.
30. Hudry E, Dashkoff J, Roe AD, Takeda S, Koffie RM,  Hashimoto T, et al. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med 2013; 5:212-235.
31. Eldik LJV, Thompson WL, Ranaivo HR, Behanna HA, Watterson DM. Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches. Int Rev Neurobiol 2007; 82:277-296.
32. Washington PM, Burns MP. The effect of the APOE4 gene on accumulation of Aβ40 after brain injury cannot be reversed by increasing APOE4 protein. J Neuropathol Exp Neurol 2016; 75:770-778.
33. Zhu Y, Nwabuisiheath E, Dumanis SB, Tai LM, Yu C, Rebeck GW, et al. APOE genotype alters glial activation and loss of synaptic markers in mice. Glia 2012; 60:559-569.
34. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001; 21:8370-8377.
35. Giri RK, Rajagopal V, Kalra VK. Curcumin, the active constituent of turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth response-1 transcription factor&nbsp. J Neurochem 2010; 91:1199-1210.
36. Li Q, Tian Z, Wang M, Kou J, Wang C, Rong X, et al. Luteoloside attenuates neuro-inflammation in focal cerebral ischemia in rats via regulation of the PPARγ/Nrf2/NF-κB signaling pathway. Int Immunopharmacol 2019; 66:309-316.
37. Zhu X, Shi J, Li H. Liquiritigenin attenuates high glucose-induced mesangial matrix accumulation, oxidative stress, and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways. Biomed pharmacother 2018; 106:976-982.
38. Cong G, Hui Q, Yingjie Y, Qiqi Z, Jia S, Donna Y, et al. The G-protein-coupled bile acid receptor Gpbar1 (TGR5) inhibits gastric inflammation through antagonizing NF-κB signaling pathway. Front Pharmacol 2015; 6:287-296.
39. Nyati KK, Masuda K, Zaman MM, Dubey PK, Millrine D, Chalise JP, et al. TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a. Nucleic Acids Res 2017; 45:2687-2703.
40. Yang S, Zhang D, Yang Z, Hu X, Qian SY, Liu J, et al. Curcumin protects dopaminergic neuron against lps induced neurotoxicity in primary rat neuron/glia culture. Neurochem Res 2008; 33:2044-2053.
41. Jin Y, Renping Liu, Yaohui Ma, Zhaoqiang Zh, Zehao X. Curcumin attenuates airway inflammation and airway remolding by inhibiting NF-κB signaling and COX-2 in cigarette smoke-induced COPD mice. Inflammation 2018; 41:1-11.
42. Hwang JS, Kang ES, Ham SA, Yoo T, Lee H, Paek KS, et al. Activation of peroxisome proliferator-activated receptor γ by rosiglitazone inhibits lipopolysaccharide-induced release of high mobility group box 1. Mediators Inflamm 2012; 2012:352807-352816.
43. Jennewein C, Kuhn AM, Schmidt MV, Meilladec-Jullig V, Knethen AV, Gonzalez FJ, et al. Sumoylation of peroxisome proliferator-activated receptor gamma by apoptotic cells prevents lipopolysaccharide-induced NCoR removal from kappab binding sites mediating transrepression of proinflammatory cytokines. J Immunol 2008; 181:5646-5652.
44. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1997; 391:79-82.