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Curcumin inhibits aggregation of α-synuclein

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Abstract

Aggregation of amyloid-beta protein (Aβ) is a key pathogenic event in Alzheimer’s disease (AD). Curcumin, a constituent of the Indian spice Turmeric is structurally similar to Congo Red and has been demonstrated to bind Aβ amyloid and prevent further oligomerization of Aβ monomers onto growing amyloid β-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation are similar in Parkinson’s disease (PD) and AD, we investigated the effect of curcumin on α-synuclein (AS) protein aggregation. In vitro model of AS aggregation was developed by treatment of purified AS protein (wild-type) with 1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin inhibited aggregation in a dose-dependent manner and increased AS solubility. The aggregation-inhibiting effect of curcumin was next investigated in cell culture utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and its aggregation examined under different concentrations of curcumin. To estimate aggregation in an unbiased manner, a protocol was developed in which the images were captured automatically through a high-throughput cell-based screening microscope. The obtained images were processed automatically for aggregates within a defined dimension of 1–6 μm. Greater than 32% decrease in mutant α-synuclein aggregation was observed within 48 h subsequent to curcumin addition. Our data suggest that curcumin inhibits AS oligomerization into higher molecular weight aggregates and therefore should be further explored as a potential therapeutic compound for PD and related disorders.

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Abbreviations

AS:

alpha-Synuclein

PD:

Parkinson’s disease

DLB:

Dementia with Lewy bodies

AD:

Alzheimer’s disease

Aβ:

Amyloid beta-protein

References

  1. Agbor GA, Oben JE, Ngogang JY, Xinxing C, Vinson JA (2005) Antioxidant capacity of some herbs/spices from cameroon: a comparative study of two methods. J Agric Food Chem 53:6819–6824

    Article  PubMed  CAS  Google Scholar 

  2. Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398

    PubMed  CAS  Google Scholar 

  3. Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB (2006) Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol 69:195–206

    PubMed  CAS  Google Scholar 

  4. Ambegaokar SS, Wu L, Alamshahi K, Lau J, Jazayeri L, Chan S, Khanna P, Hsieh E, Timiras PS (2003) Curcumin inhibits dose-dependently and time-dependently neuroglial cell proliferation and growth. Neuro Endocrinol Lett 24:469–473

    PubMed  CAS  Google Scholar 

  5. Annabi B, Lachambre MP, Bousquet-Gagnon N, Page M, Gingras D, Beliveau R (2002) Green tea polyphenol (-)-epigallocatechin 3-gallate inhibits MMP-2 secretion and MT1-MMP-driven migration in glioblastoma cells. Biochim Biophys Acta 1542:209–220

    Article  PubMed  CAS  Google Scholar 

  6. Baum L, Ng A (2004) Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer’s disease animal models. J Alzheimers Dis 6:367–377; discussion 443–9

    PubMed  CAS  Google Scholar 

  7. Behari M, Bhatnagar SP, Muthane U, Deo D (2002) Experiences of Parkinson’s disease in India. Lancet Neurol 1:258–262

    Article  PubMed  Google Scholar 

  8. Bevis BJ, Glick BS (2002) Rapidly maturing variants of the Discosoma red fluorescent protein (DsRed). Nat Biotechnol 20:83–87

    Article  PubMed  CAS  Google Scholar 

  9. Caughey B, Raymond LD, Raymond GJ, Maxson L, Silveira J, Baron GS (2003) Inhibition of protease-resistant prion protein accumulation in vitro by curcumin. J Virol 77:5499–5502

    Article  PubMed  CAS  Google Scholar 

  10. Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang YJ, Tsai CC, Hsieh CY (2001) Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21:2895–2900

    PubMed  CAS  Google Scholar 

  11. Choi HK, Won L, Roback JD, Wainer BH, Heller A (1992) Specific modulation of dopamine expression in neuronal hybrid cells by primary cells from different brain regions. Proc Natl Acad Sci USA 89:8943–8947

    Article  PubMed  CAS  Google Scholar 

  12. Cole GM, Lim GP, Yang F, Teter B, Begum A, Ma Q, Harris-White ME, Frautschy SA (2005) Prevention of Alzheimer’s disease: omega-3 fatty acid and phenolic anti-oxidant interventions. Neurobiol Aging 26(Suppl 1):133–136

    Article  PubMed  CAS  Google Scholar 

  13. Commandeur JN, Vermeulen NP (1996) Cytotoxicity and cytoprotective activities of natural compounds. The case of curcumin. Xenobiotica 26:667–680

    Article  PubMed  CAS  Google Scholar 

  14. Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 4:1318–1320

    Article  PubMed  CAS  Google Scholar 

  15. Conway KA, Harper JD, Lansbury PT Jr (2000) Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 39:2552–2263

    Article  PubMed  CAS  Google Scholar 

  16. Craig WJ (1999) Health-promoting properties of common herbs. Am J Clin Nutr 70:491S–499S

    PubMed  CAS  Google Scholar 

  17. Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF, Dawson VL, Dawson TM, Ross CA (1999) Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 22:110–114

    Article  PubMed  CAS  Google Scholar 

  18. Eriksen JL, Dawson TM, Dickson DW, Petrucelli L (2003) Caught in the act: alpha-synuclein is the culprit in Parkinson’s disease. Neuron 40:453–456

    Article  PubMed  CAS  Google Scholar 

  19. Frei B, Higdon JV (2003) Antioxidant activity of tea polyphenols in vivo: evidence from animal studies. J Nutr 133:3275S–3284S

    PubMed  CAS  Google Scholar 

  20. Galvin JE, Giasson B, Hurtig HI, Lee VM, Trojanowski JQ (2000) Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am J Pathol 157:361–368

    PubMed  CAS  Google Scholar 

  21. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533

    Article  PubMed  CAS  Google Scholar 

  22. Hasegawa T, Matsuzaki M, Takeda A, Kikuchi A, Akita H, Perry G, Smith MA, Itoyama Y (2004) Accelerated alpha-synuclein aggregation after differentiation of SH-SY5Y neuroblastoma cells. Brain Res 1013:51–59

    Article  PubMed  CAS  Google Scholar 

  23. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E (1999) Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport 10:717–721

    Article  PubMed  CAS  Google Scholar 

  24. Jana NR, Tanaka M, Wang G, Nukina N (2000) Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum Mol Genet 9:2009–2018

    Article  PubMed  CAS  Google Scholar 

  25. Jana NR, Dikshit P, Goswami A, Nukina N (2004) Inhibition of proteasomal function by curcumin induces apoptosis through mitochondrial pathway. J Biol Chem 279:11680–11685

    Article  PubMed  CAS  Google Scholar 

  26. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300:486–489

    Article  PubMed  CAS  Google Scholar 

  27. Lau FC, Shukitt-Hale B, Joseph JA (2005) The beneficial effects of fruit polyphenols on brain aging. Neurobiol Aging 26(Suppl 1):128–132

    Article  PubMed  CAS  Google Scholar 

  28. Lee CS, Tee LY, Warmke T, Vinjamoori A, Cai A, Fagan AM, Snider BJ (2004) A proteasomal stress response: pre-treatment with proteasome inhibitors increases proteasome activity and reduces neuronal vulnerability to oxidative injury. J Neurochem 91:996–1006

    Article  PubMed  CAS  Google Scholar 

  29. Lee HJ, Khoshaghideh F, Patel S, Lee SJ (2004) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24:1888–1896

    Article  PubMed  CAS  Google Scholar 

  30. Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280:37377–37382

    Article  PubMed  CAS  Google Scholar 

  31. McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P (2001) Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci 2:589–594

    Article  PubMed  CAS  Google Scholar 

  32. McNaught KS, Bjorklund LM, Belizaire R, Isacson O, Jenner P, Olanow CW (2002) Proteasome inhibition causes nigral degeneration with inclusion bodies in rats. Neuroreport 13:1437–1441

    Article  PubMed  CAS  Google Scholar 

  33. Ono K, Yamada M (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem 97:105–115

    Article  PubMed  CAS  Google Scholar 

  34. Pandey N, Schmidt RE, Galvin JE (2006) The alpha-synuclein mutation E46K promotes aggregation in cultured cells. Exp Neurol 197:515–520

    Article  PubMed  CAS  Google Scholar 

  35. Prasad JE, Kumar B, Andreatta C, Nahreini P, Hanson AJ, Yan XD, Prasad KN (2004) Overexpression of alpha-synuclein decreased viability and enhanced sensitivity to prostaglandin E(2), hydrogen peroxide, and a nitric oxide donor in differentiated neuroblastoma cells. J Neurosci Res 76:415–422

    Article  PubMed  CAS  Google Scholar 

  36. Ragothaman M, Murgod UA, Gururaj G, Kumaraswamy SD, Muthane U (2003) Lower risk of Parkinson’s disease in an admixed population of European and Indian origins. Mov Disord 18:912–914

    Article  PubMed  Google Scholar 

  37. Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, Heber D (2005) In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem 16:360–367

    Article  PubMed  CAS  Google Scholar 

  38. Singh S, Aggarwal BB (1995) Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 270:24995–25000

    Article  PubMed  CAS  Google Scholar 

  39. Stefanova N, Klimaschewski L, Poewe W, Wenning GK, Reindl M (2001) Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 65:432–438

    Article  PubMed  CAS  Google Scholar 

  40. Venkatesan P, Rao MN (2000) Structure-activity relationships for the inhibition of lipid peroxidation and the scavenging of free radicals by synthetic symmetrical curcumin analogues. J Pharm Pharmacol 52:1123–1128

    Article  PubMed  CAS  Google Scholar 

  41. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280:5892–5901

    Article  PubMed  CAS  Google Scholar 

  42. Yarbrough D, Wachter RM, Kallio K, Matz MV, Remington SJ (2001) Refined crystal structure of DsRed, a red fluorescent protein from coral, at 2.0-A resolution. Proc Natl Acad Sci USA 98:462–467

    Article  PubMed  CAS  Google Scholar 

  43. Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT (2005) Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease. Free Radic Res 39:1119–1125

    Article  PubMed  CAS  Google Scholar 

  44. Zhang X, Xie W, Qu S, Pan T, Wang X, Le W (2005) Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration. Biochem Biophys Res Commun 333:544–549

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Dr. Michele Goedert for the AS construct. We are grateful to Dr. John Trojanowski for antibodies. We would like to thank Dr. Alfred Heller for gifting the MN9D cell line. This work was supported by grants from the American Federation on Aging Research and the National Institute on Aging (K08 AG20764). Dr. Galvin is a recipient of the Paul Beeson Physician Faculty Scholar Award in Aging Research. This project was also supported by generous gifts from the Alan A. and Edith L. Wolff Charitable Trust and the Blue Gator Foundation. Dr. Pandey was partly supported by Missouri Alzheimer Disease and Related Disorder Program for this work.

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, 63110, USA

    Neeraj Pandey

  2. Department of Neuropathology, Washington University School of Medicine, St Louis, MO, 63110, USA

    Jeffrey Strider

  3. Department of Biochemistry and Molecular Biology, Washington University School of Medicine, St Louis, MO, 63110, USA

    William C. Nolan

  4. Department of Neurology, Washington University School of Medicine, St Louis, MO, 63110, USA

    Sherry X. Yan & James E. Galvin

  5. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, 63110, USA

    James E. Galvin

  6. Alzheimer Disease Research Center, Department of Neurobiology, Washington University School of Medicine, 4488 Forest Park, Suite 130, St Louis, MO, 63108, USA

    James E. Galvin

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  1. Neeraj Pandey
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  2. Jeffrey Strider
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  3. William C. Nolan
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Correspondence to James E. Galvin.

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Pandey, N., Strider, J., Nolan, W.C. et al. Curcumin inhibits aggregation of α-synuclein. Acta Neuropathol 115, 479–489 (2008). https://doi.org/10.1007/s00401-007-0332-4

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  • DOI: https://doi.org/10.1007/s00401-007-0332-4

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