The Korean Journal of Physiology and Pharmacology

  • 제13권4호
  • /
  • Pages.273-279
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  • 2009
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  • 1226-4512(pISSN)
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  • 2093-3827(eISSN)
대한약리학회 (The Korean Society of Pharmacology)
권호 표지

Inhibition of ${\beta}-amyloid_{1-40}$ Peptide Aggregation and Neurotoxicity by Citrate

  • Park, Yong-Hoon (Inam Neuroscience Research Center College of Medicine, Wonkwang University) ;
  • Kim, Young-Jin (Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University) ;
  • Son, Il-Hong (Inam Neuroscience Research Center College of Medicine, Wonkwang University) ;
  • Yang, Hyun-Duk (Inam Neuroscience Research Center College of Medicine, Wonkwang University)
  • 발행 : 2009.08.31
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⟨ 이전 논문 다음 논문 ⟩

초록

The accumulation of ${\beta}$-amyloid (A${\beta}$) aggregates is a characteristic of Alzheimer's disease (AD). Furthermore, these aggregates have neurotoxic effects on cells, and thus, molecules that inhibit A${\beta}$ aggregate formation could be valuable therapeutics for AD. It is well known that aggregation of A${\beta}$ depends on its hydrophobicity, and thus, in order to increase the hydrophilicity of A${\beta}$, we considered using citrate, an anionic surfactant with three carboxylic acid groups. We hypothesized that citrate could reduce hydrophobicity and increase hydrophilicity of A${\beta}_{1-40}$ molecules via hydrophilic/electrostatic interactions. We found that citrate significantly inhibited A${\beta}_{1-40}$ aggregation and significantly protected SH-SY5Y cell line against A${\beta}_{1-40}$ aggregates-induced neurotoxicity. In details, we examined the effects of citrate on A${\beta}_{1-40}$ aggregation and on A${\beta}_{1-40}$ aggregates-induced cytotoxicity, cell viability, and apoptosis. Th-T assays showed that citrate significantly inhibited A${\beta}_{1-40}$ aggregation in a concentration-dependent manner (Th-T intensity: from 91.3% in 0.01 mM citrate to 82.1% in 1.0 mM citrate vs. 100.0% in A${\beta}_{1-40}$ alone). In cytotoxicity and viability assays, citrate reduced the toxicity of A${\beta}_{1-40}$ in a concentration-dependent manner, in which the cytotoxicity decreased from 107.5 to 102.3% as compared with A${\beta}_{1-40}$ aggregates alone treated cells (127.3%) and the cell viability increased from 84.6 to 93.8% as compared with the A${\beta}_{1-40}$ aggregates alone treated cells (65.3%). Furthermore, Hoechst 33342 staining showed that citrate (1.0 mM) suppressed A${\beta}_{1-40}$ aggregates-induced apoptosis in the cells. This study suggests that citrate can inhibit A${\beta}_{1-40}$ aggregation and protect neurons from the apoptotic effects of A${\beta}_{1-40}$ aggregates. Accordingly, our findings suggest that citrate administration should be viewed as a novel neuroprotective strategy for AD.

키워드

참고문헌

  1. Ban T, Hoshino M, Takahashi S, Hamada D, Hasegawa K, Naiki H, Goto Y. Direct observation of Abeta amyloid fibril growth and inhibition. J Mol Biol 344: 757−767, 2004 https://doi.org/10.1016/j.jmb.2004.09.078
  2. Barrow CJ, Zagorski MG. Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition. Science 253: 179−182, 1991 https://doi.org/10.1126/science.1853202
  3. Bokvist M, Lindstrom F, Watts A, Grobner G. Two types of Alzheimer's beta-amyloid (1-40) peptide membrane interactions: aggregation preventing transmembrane anchoring versus accelerated surface fibril formation. J Mol Biol 335: 1039−1049, 2004 https://doi.org/10.1016/j.jmb.2003.11.046
  4. Brus L. Noble metal nanocrystals: plasmon electron transfer photochemistry and single-molecule raman spectroscopy. Acc Chem Res 41: 1742−1749, 2008 https://doi.org/10.1021/ar800121r
  5. Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP, Gusella JF, Beyreuther K, Masters CL, Tanzi RE. Rapid induction of Alzheimer Abeta amyloid formation by zinc. Science 265: 1464−1467, 1994 https://doi.org/10.1126/science.8073293
  6. Cao M, Han Y, Wang J, Wang Y. Modulation of fibrillogenesis of amyloid $\beta$ (1-40) peptide with cationic gemini surfactant. J Phys Chem B 111: 13436−13443, 2007 https://doi.org/10.1021/jp075271b
  7. Citron M. Strategies for disease modification in Alzheimer's disease. Nat Rev Neurosci 5: 677−685, 2004 https://doi.org/10.1038/nrn1495
  8. Cummings JL, Doody R, Clark C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology 69: 1622−1634, 2007 https://doi.org/10.1212/01.wnl.0000295996.54210.69
  9. Gschwind M, Huber G. Apoptotic cell death induced by beta-amyloid 1-42 peptide is cell type dependent. J Neurochem 65: 292−300, 1995 https://doi.org/10.1046/j.1471-4159.1995.65010292.x
  10. Halverson K, Fraser PE, Kirschner DA, Lansbury PT Jr. Molecular determinants of amyloid deposition in Alzheimer's disease: conformational studies of synthetic beta-protein fragments. Biochemistry 29: 2639−2644, 1990 https://doi.org/10.1021/bi00463a003
  11. Hensley K, Carney JM, Mattson MP, Aksenova MV, Harris ME, Wu JF, Floyd RA, Butterfield DA. A model for $\beta$-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA 91: 3270−3274, 1994 https://doi.org/10.1073/pnas.91.8.3270
  12. Howlett DR, Jennings KH, Lee DC, Clark MS, Brown F, Wetzel R, Wood SJ, Camilleri P, Roberts GW. Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide. Neurodegeneration 4: 23−32, 1995 https://doi.org/10.1006/neur.1995.0003
  13. Jarrett JT, Berger EP, Lansbury Jr. PT. The carboxy terminus of the $\beta$-amyloid protein is critical for the seeding of amyloid formation: implication for the pathogenesis of Alzheimer's disease. Biochemistry 32: 4693−4697, 1993 https://doi.org/10.1021/bi00069a001
  14. Jeng US, Lin TL, Lin JM, Ho DL. Contrast variation SANS for the solution structure of the $\beta$-amyloid peptide1-40 influenced by SDS surfactants. Physica B 385−386: 865−867, 2006 https://doi.org/10.1016/j.physb.2006.05.128
  15. Ji SR, Wu Y, Sui SF. Study of beta-amyloid peptide (Abeta40) insertion into phospholipid membranes using monolayer technique. Biochemistry (Mosc) 67: 1283−1288, 2002 https://doi.org/10.1023/A:1021361607611
  16. Khandogin J, Brooks III CL. Linking folding with aggregation in Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci USA 104: 16880−16885, 2007 https://doi.org/10.1073/pnas.0703832104
  17. Kisilevsky R, Lemieux LJ, Fraser PE, Kong X, Hultin PG, Szarek WA. Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease. Nat Med 1: 143−148, 1995 https://doi.org/10.1038/nm0295-143
  18. Koh JY, Yang LLY, Cotman CW. Beta-amyloid protein increases vulnerability of cultured neurons to excitotoxins. Brain Res 533: 315−320, 1990 https://doi.org/10.1016/0006-8993(90)91355-K
  19. Lazo ND, Grant MA, Condron MC, Rigby AC, Teplow DB. On the nucleation of amyloid beta-protein monomer folding. Protein Sci 14: 1581−1596, 2005 https://doi.org/10.1110/ps.041292205
  20. Lizard G, Fournel S, Genestier L, Dhedin N, Chaput C, Flacher M, Mutin M, Panaye G, Revillard JP. Kinetics of plasma membrane and mitochondrial alterations in cells undergoing apoptosis. Cytometry 21: 275−283, 1995 https://doi.org/10.1002/cyto.990210308
  21. Lomakin A, Chung DS, Benedek GB, Kirschner DA, Teplow DB. On the nucleation and growth of amyloid beta-protein fibrils: Detection of nuclei and quantitation of rate constants. Proc Natl Acad Sci USA 93: 1125−1129, 1996 https://doi.org/10.1073/pnas.93.3.1125
  22. Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc Natl Acad Sci USA 91: 12243−12247, 1994 https://doi.org/10.1073/pnas.91.25.12243
  23. Lowe TL, Strzelec A, Kiessling LL, Murphy RM. Structure-function relationships for inhibitors of beta-amyloid toxicity containing the recognition sequence KLVFF. Biochemistry 40: 7882−7889, 2001 https://doi.org/10.1021/bi002734u
  24. Luhrs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Dobeli H, Schubert D, Riek R. 3D structure of Alzheimer's amyloid-$\beta$ (1-42) fibrils. Proc Natl Acad Sci USA 102: 17342−17347, 2005 https://doi.org/10.1073/pnas.0506723102
  25. Marcinowski KJ, Shao H, Clancy EL, Zagorski MG. Solution structure model of residues 1-28 of the amyloid beta peptide when bound to micelles. J Am Chem Soc 120: 11082−11091, 1998 https://doi.org/10.1021/ja9738687
  26. McConnell S, Riggs J. Alzheimer's research: can it help save our nation's entitlement programs? Alzheimer Dementia 1: 84−86, 2005 https://doi.org/10.1016/j.jalz.2005.06.005
  27. Mook-Jung I, Joo I, Sohn S, Kwon HJ, Huh K, Jung MW. Estrogen blocks neurotoxic effects of beta-amyloid (1-42) and induces neurite extension in B103 cells. Neurosci Lett 235: 101−104, 1997 https://doi.org/10.1016/S0304-3940(97)00632-0
  28. Nowick JS, Lam KS, Khasanova TV, Kemnitzer WE, Maitra S, Mee HT, Liu R. An unnatural amino acid that induces beta-sheet folding and interaction in peptides. J Am Chem Soc 124: 4972−4973, 2002 https://doi.org/10.1021/ja025699i
  29. Pallitto MM, Ghanta J, Heinzelman P, Kiessling LL, Murphy RM. Recognition sequence design for peptidyl modulators of beta- amyloid aggregation and toxicity. Biochemistry 38: 3570−3578, 1999 https://doi.org/10.1021/bi982119e
  30. Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghiso J. Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem 273: 7185−7188, 1998 https://doi.org/10.1074/jbc.273.13.7185
  31. Pereira C, Agostinho P, Moreira PI, Cardoso SM, Oliveira CR. Alzheimer's disease-associated neurotoxic mechanisms and neuroprotective strategies. Curr Drug Targets CNS Neurol Disord 4: 383−403, 2005 https://doi.org/10.2174/1568007054546117
  32. Pike CJ, burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by $\beta$-amyloid peptides in vitro: the role of peptide assembly state. J Neruosci 13: 1676−1687, 1993
  33. Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW. Aggregation related toxicity of synthetic beta-amyloid protein in hippocampal cultures, Eur J Pharmacol 207: 367−368, 1991 https://doi.org/10.1016/0922-4106(91)90014-9
  34. Pike CJ, Walencewicz-Wasserman AJ, Kosmoski J, Cribbs DH, Glabe CG, Cotman CW. Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity. J Neurochem 64: 253−265, 1995 https://doi.org/10.1046/j.1471-4159.1995.64010253.x
  35. Puntel RL, Roos DH, Grotto D, Garcia SC, Nogueira CW, Rocha JB. Antioxidant properties of Krebs cycle intermediates against malonate pro-oxidant activity in vitro: a comparative study using the colorimetric method and HPLC analysis to determine malondialdehyde in rat brain homogenates. Life Sci 81: 51−62, 2007 https://doi.org/10.1016/j.lfs.2007.04.023
  36. Rangachari V, Reed DK, Moore BD, Rosenberry TL. Secondary structure and interfacial aggregation of amyloid-beta (1-40) on sodium dodecyl sulfate micelles. Biochemistry 45: 8639−8648, 2006 https://doi.org/10.1021/bi060323t
  37. Rochet JC Jr, Lansbury PT. Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol 10: 60−68, 2000 https://doi.org/10.1016/S0959-440X(99)00049-4
  38. Sabate R, Gallardo M, Estelrich J. An autocatalytic reaction as a model for the kinetics of the aggregation of beta-amyloid. Biopolymers 71: 190−195, 2003 https://doi.org/10.1002/bip.10441
  39. Sabate R, Estelrich J. Evidence of the existence of micelles in the fibrillogenesis of beta-amyloid peptide. J Phys Chem B 109: 11027−11032, 2005a https://doi.org/10.1021/jp050716m
  40. Sabate R, Estelrich J. Stimulatory and inhibitory effects of alkyl bromide surfactants on beta-amyloid fibrillogenesis. Langmuir 21: 6944−6949, 2005b https://doi.org/10.1021/la050472x
  41. Salomon AR, Marcinowski KJ, Friedland RW, Zagorski MG. Nicotine inhibits amyloid formation by the beta-peptide. Biochemistry 35: 13568−13578, 1996. https://doi.org/10.1021/bi9617264
  42. Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer's disease: current status and new perspectives. Lancet Neurol 2: 539−547, 2003 https://doi.org/10.1016/S1474-4422(03)00502-7
  43. Seiffert D, Bradley JD, Rominger CM, Rominger DH, Yang F, Meredith JE Jr, Wang Q, Roach AH, Thompson LA, Spitz SM, Higaki JN, Prakash SR, Combs AP, Copeland RA, Arneric SP, Hartig PR, Robertson DW, Cordell B, Stern AM, Olson RE, Zaczek R. Presenilin-1 and -2 are molecular targets for gamma- secretase inhibitors. J Biol Chem 275: 34086−34091, 2000 https://doi.org/10.1074/jbc.M005430200
  44. Seilheimer B, Bohrmann B, Bondolfi L, M$\ddot{u}$ller F, Stuber D, Dobeli H. The toxicity of the Alzheimer's beta-amyloid peptide correlates with a distinct fiber morphology. J Struct Biol 119: 59−71, 1997 https://doi.org/10.1006/jsbi.1997.3859
  45. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81: 741−766, 2001
  46. Sisodia SS, St George-Hyslop PH. Gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in? Nat Rev Neurosci 3: 281−290, 2002 https://doi.org/10.1038/nrn785
  47. Snyder SW, Ladror US, Wade WS, Wang GT, Barrett LW, Matayoshi ED, Huffaker HJ, Krafft GA, Holzman TF. Amyloid- beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths. Biophys J 67: 1216−1228, 1994 https://doi.org/10.1016/S0006-3495(94)80591-0
  48. Soreghan B, Kosmoski J, Glabe C. Surfactant properties of Alzheimer's Abeta peptides and the mechanism of amyloid aggregation. J Biol Chem 269: 28551−28554, 1994
  49. Wang SS, Chen YT, Chou SW. Inhibition of amyloid fibril formation of beta-amyloid peptides via the amphiphilic surfactants. Biochim Biophys Acta 1741: 307−313, 2005 https://doi.org/10.1016/j.bbadis.2005.05.004
  50. Watanabe K, Segawa T, Nakamura K, Kodaka M, Konakahara T, Okuno H. Identification of the molecular-interaction site of amyloid beta peptide by using a fluorescence assay. J Pept Res 58: 342−346, 2001 https://doi.org/10.1034/j.1399-3011.2001.00920.x
  51. Wood SJ, MacKenzie L, Maleeff B, Hurle MR, Wetzel R. Selective inhibition of Abeta fibril formation. J Biol Chem 271: 4086−4092, 1996a https://doi.org/10.1074/jbc.271.8.4086
  52. Wood SJ, Maleeff B, Hart T, Wetzel R. Physical, morphological and functional differences between ph 5.8 and 7.4 aggregates of the Alzheimer's amyloid peptide Abeta. J Mol Biol 256: 870−877, 1996b https://doi.org/10.1006/jmbi.1996.0133
  53. Yang HD, Son IH, Lee SS, Park YH. Protective effect of citrate against A$\beta$-induced neurotoxicity in PC12 cells. Mol Cell Toxicol 4: 157−163, 2008
  54. Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 16: 921−932, 1996 https://doi.org/10.1016/S0896-6273(00)80115-4