Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Effect of Reserpine on the Behavioral Defects, Aβ-42 Deposition and NGF Metabolism in Tg2576 Transgenic Mouse Model for Alzheimer's Disease

알츠하이머질환 모델동물인 Tg2576마우스의 행동, Aβ-42 침적, 신경성장인자 대사에 미치는 reserpine의 영향

  • Go, Jun (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Choi, Sun Il (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Kim, Ji Eun (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Lee, Young Ju (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Kwak, Moon Hwa (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Koh, Eun Kyoung (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Song, Sung Hwa (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Sung, Ji Eun (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Hwang, Dae Youn (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University)
  • 고준 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 최선일 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 김지은 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 이영주 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 곽문화 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 고은경 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 송성화 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 성지은 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 황대연 (부산대학교 생명자원과학대학 바이오소재과학과)
  • Received : 2013.03.25
  • Accepted : 2013.06.17
  • Published : 2013.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Reserpine, an anti-hypertensive drug, is able to positively modulate several phenotypes associated with $A{\beta}$ toxicity in a Caenorhabditis elegans model of Alzheimer's disease (AD). We investigated into the therapeutic effects of reserpine on mammalian neurodegenerative disorders, and found that significant alteration of the key factors influencing AD was detected in Tg2576 mice after reserpine treatment for 30 days. The aggressive behavior of Tg2576 mice was significantly improved upon reserpine treatment, whereas their social contact was consistently maintained. Furthermore, the levels of $A{\beta}$-42 peptide in the hippocampus of the brain and blood serum were lower in the reserpine-treated group than in the vehicle-treated group. Among g-secretase components, the expression levels of PS-2, Pen-2, and APH-1 were slightly lower in reserpine-treated Tg2576 mice, although a significant change in nicastrin (NCT) expression was not detected. Furthermore, the serum level of nerve growth factor (NGF) increased in reserpine-treated Tg2576 mice compared with vehicle-treated mice. Among down-stream effectors of the NGF receptor TrkA signaling pathway, reserpine treatment induced elevation of TrkA phosphorylation and reduction of ERK phosphorylation. In addition, in the NGF receptor $p75^{NTR}$ signaling pathway, the expression levels of $p75^{NTR}$ and Bcl-2 were enhanced in reserpine-treated Tg2576 mice compared with vehicle-treated mice, whereas the expression level of RhoA declined. Overall, these results suggest that reserpine can help relieve AD pathogenesis in Tg2576 mice through downregulation of $A{\beta}$-42 deposition, alteration of ${\gamma}$-secretase components, and regulation of NGF metabolism.

Reserpine은 항고혈압제로서 알츠하이머질병의 증상을 나타내는 Caenorhabditis elegans에서 세포독성을 감소시켜 마비를 억제하고 수명을 연장시키는 것으로 알려져 있다. 본 연구에서는 이러한 reserpine의 효능을 포유동물에서 확인하기 위하여, 알츠하이머질병의 병리적 특성과 연관된 주요인자의 변화를 30일 동안 reserpine을 투여한 Tg2576 마우스에서 관찰하였다. 그 결과, 공격행동(aggressive behavior)은 vehicle 투여 그룹에 비하여 reserpine 투여 그룹에서 유의적으로 감소하였으나 사회적 접촉(social contact)은 유의적인 변화가 없었다. 뇌의 해마부분에서 알츠하이머질병의 원인 중 하나인 $A{\beta}$-42의 축적은 reserpine 투여 그룹에서 유의적으로 감소하였고, $A{\beta}$-42의 농도도 대조군에 비하여 reserpine 투여 그룹에서 감소하였다. 더불어, ${\gamma}$-secretase의 구성단백질 중에서 PS-2, Pen-2, APH-1의 발현은 대조군에 비하여 reserpine 투여군에서 유의적으로 감소하였으나 NCT 발현은 변화가 없었다. 혈청에서 NGF의 농도는 Tg2576 마우스에서 감소하였다가 reserpine 투여한 그룹에서 유의적으로 증가하였으며, high affinity receptor의 신호전달과정에 포함된 단백질 중에서 reserpine 투여 그룹은 TrkA의 인산화가 증가하고 ERK 인산화는 감소되었다. 한편 low affinity receptor의 신호전달과정에서, $p75^{NTR}$과 Bcl-2의 발현은 vehicle 그룹에 비하여 reserpine 투여 그룹에서 유의적으로 발현이 증가하였으나 RhoA의 발현은 reserpine 투여 그룹에서 감소하였다. 따라서 이러한 결과는 reserpine은 포유동물 치매모델인 Tg2576 마우스에서 행동학적 변화, $A{\beta}$-42의 축적, NGF의 농도, NGF신호전달의 변화 등을 유도하며, 향후 치매치료제로서 가능성을 제시하고 있다.

Keywords

References

  1. Ahn, K., Shelton, C. C., Tian, Y., Zhang, X., Gilchrist, M. L., Sisodia, S. S. and Li, Y. M. 2010. Activation and intrinsic gamma-secretase activity of presenilin 1. Proc Natl Acad Sci USA 107, 21435-21440. https://doi.org/10.1073/pnas.1013246107
  2. Arendt, T. 2009. Synaptic degeneration in Alzheimer's disease. Acta Neuropathol 118, 167-179. https://doi.org/10.1007/s00401-009-0536-x
  3. Arya, U., Dwivedi, H. and Subramaniam, J. R. 2009. Reserpine ameliorates Abeta toxicity in the Alzheimer's disease model in Caenorhabditis elegans. Exp Gerontol 44, 462-466. https://doi.org/10.1016/j.exger.2009.02.010
  4. Behl, C., Davis, J. B., Lesley, R. and Schubert, D. 1994. Hydrogen peroxide mediates amyloid ${\beta}$ protein toxicity. Cell 77, 817-827. https://doi.org/10.1016/0092-8674(94)90131-7
  5. Blennow, K., de Leon, M. J. and Zetterberg, H. 2006. Alzheimer's disease. Lancet 368, 387-403. https://doi.org/10.1016/S0140-6736(06)69113-7
  6. Bleuler, M. and Stoll, W. A. 1955. Clinical use of reserpine in psychiatry: comparison with chlorpromazine. Ann N Y Acad Sci 61, 167-173. https://doi.org/10.1111/j.1749-6632.1955.tb42463.x
  7. Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., Prada, C. M., Kim, G., Seekin, S., Yager, D., Slunt, H. H., Wang, R., Seeger, M., Levey, A. I., Gandy, S. E., Copeland, N. G., Jenkins, N. A., Price, D. L., Younkin, S. G. and Sisodia, S. S. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta 1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005-1013.
  8. Carmichael, S. W., Weber, A. and Winkler, H. 1980. Uptake of nucleotides and catecholamines by chromaffin granules from pig and horse adrenal medulla. J Neurochem 35, 270-272. https://doi.org/10.1111/j.1471-4159.1980.tb12516.x
  9. Cavallucci, V., D’Amelio, M. and Cecconi, F. 2012. A${\beta}$ toxicity in Alzheimer’s disease. Mol Neurobiol 45, 366-378. https://doi.org/10.1007/s12035-012-8251-3
  10. Cerejeira, J., Lagarto, L. and Mukaetova-Ladinska, E. B. 2012. Behavioral and psychological symptoms of Dementia. Front Neurol 3, 1-21.
  11. Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I. and Selkoe, D. J. 1992. Mutation of the ${\beta}$-amyloid precursor protein in familial Alzheimer's disease increases protein production. Nature 360, 672-674. https://doi.org/10.1038/360672a0
  12. di Mola, F. F., Friess, H., Zhu, Z. W., Koliopanos, A., Bley, T., Di sebastiano, P., Innocenti, P., Zimmermann, A. and Bu chler, M. W. 2000. Nerve growth factor and Trk high affinity receptor (TrkA) gene expression in inflammatory bowel disease. Gut 46, 670-679. https://doi.org/10.1136/gut.46.5.670
  13. Einarsdottir, E., Carlsson, A., Minde, J., Toolanen, G., Svensson, O., Solders, G., Holmgren, G., Holmberg, D. and Holmberg, M. 2004. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet 13, 799-805. https://doi.org/10.1093/hmg/ddh096
  14. Fabrazzo, M., Costa, E. and Mocchetti, I. 1991. Stimulation of nerve growth factor biosynthesis in developing rat brain by reserpine: steroids as potential mediators. Mol Pharmacol 39, 144-149.
  15. Frautschy, S. A., Baird, A. and Cole, G. M. 1991. Effects of injected Alzheimer ${\beta}$-amyloid cores in rat brain. Proc Natl Acad Sci USA 88, 8362-8266. https://doi.org/10.1073/pnas.88.19.8362
  16. Frautschy, S. A., Yang, F., Irrizarry, M., Hyman, B., Saido, T., Hsiao, K. and Cole, G. 1998. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152, 307-317.
  17. Freund-Michel, V. and Frossard, N. 2008. The nerve growth factor and its receptors in airway inflammatory diseases. Pharmacol Ther 117, 52-76. https://doi.org/10.1016/j.pharmthera.2007.07.003
  18. Fujiwara, H., Takayama, S., Iwasaki, K., Tabuchi, M., Yamaguchi, T., Sekiguchi, K., Ikarashi, Y., Kase, Y., Arai, H. and Yaegashi, N. 2011. Yokukansan, a traditional Japanese medicine, ameliorates memory disturbance and abnormal social interaction with anti-aggregation effect of cerebral amyloid ${\beta}$ proteins in amyloid precursor protein transgenic mice. Neuroscience 180, 305-313. https://doi.org/10.1016/j.neuroscience.2011.01.064
  19. Goedert, M. and Spillantini, M. G. 2006. A century of Alzheimer's disease. Science 314, 777-781. https://doi.org/10.1126/science.1132814
  20. Haass, C., Lemere, C. A., Capell, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L. and Selkoe, D. J. 1995. The Swedish mutation causes earlyonset Alzheimer's disease by ${\beta}$-secretase cleavage within the secretory pathway. Nature Med 1, 1291-1296. https://doi.org/10.1038/nm1295-1291
  21. Heese, K., Low, J. W. and Inoue, N. 2006. Nerve growth factor, Neural stem cells and Alzheimer's disease. Neurosignals 15, 1-12. https://doi.org/10.1159/000094383
  22. Henry, J. P., Gasnier, B., Roisin, M. P., Isambert, M. F. and Scherman, D. 1987. Molecular pharmacology of the monoamine transporter of the chromaffin granule membrane. Ann N Y Acad Sci 493, 194-206. https://doi.org/10.1111/j.1749-6632.1987.tb27201.x
  23. Henry, J. P., Sagne, C., Botton, D., Isambert, M. F. and Gasnier, B. 1998. Molecular pharmacology of the vesicular monoamine transporter. Adv Pharmacol 42, 236-239.
  24. Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F. and Cole, G. 1996. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99-102. https://doi.org/10.1126/science.274.5284.99
  25. Hwang, D. Y., Chae, K. R., Kang, T. S., Hwang, J. H., Lim, C. H., Kang, H. K., Goo, J. S., Lee, M. R., Lim, H. J., Min, S. H., Cho, J. Y., Hong, J. T., Song, C. W., Paik, S. G., Cho, J. S. and Kim, Y. K. 2002. Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer's disease. FASEB J 16, 805-813. https://doi.org/10.1096/fj.01-0732com
  26. Iwatsubo, T. 2004. The ${\gamma}$-secretase complex: machinery for intramembrane proteolysis. Curr Opin Neurobiol 14, 379-383. https://doi.org/10.1016/j.conb.2004.05.010
  27. Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S. and Malinow, R. 2003. APP processing and synaptic function. Neuron 37, 925-937. https://doi.org/10.1016/S0896-6273(03)00124-7
  28. Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S. and Selkoe, D. J. 2003. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, And Pen-2. Proc Natl Acad Sci USA 100, 6382-6387. https://doi.org/10.1073/pnas.1037392100
  29. King, D. L. and Arendash, G. W. 2002. Behavioral characterization of the Tg2576 transgenic model of Alzheimer’s disease through 19 months. Physiol Behav 75, 627-642. https://doi.org/10.1016/S0031-9384(02)00639-X
  30. Kirshner, N. 1962. Uptake of catecholamines by a particulate fraction of the adrenal medulla. J Biol Chem 237, 2311-2317.
  31. Kirshner, N. 1962. Uptake of catecholamines by a particulate fraction of the adrenal medulla. Science 135, 107-108. https://doi.org/10.1126/science.135.3498.107
  32. Kowall, N. W., Beal, M. F., Busciglio, J., Duffy, L. K. and Yankner, B. A. 1991. An in vivo model for the neurodegenerative effects of ${\beta}$ amyloid and protection by substance P. Proc Nat Acad Sci USA 88, 7247-7251. https://doi.org/10.1073/pnas.88.16.7247
  33. Levitan, D., Lee, J., Song, L., Manning, R., Wong, G., Parker, E. and Zhang, L. 2001. PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling. Proc Natl Acad Sci USA 98, 12186-12190. https://doi.org/10.1073/pnas.211321898
  34. Link, C. D. 1995. Expression of human-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci 92, 9368-9372. https://doi.org/10.1073/pnas.92.20.9368
  35. Li, Y. M., Lai, M. T., Xu, M., Huang, Q., DiMuzio-Mower, J., Sardana, M. K., Shi, X. P., Yin, K. C., Shafer, J. A. and Gardell, S. J. 2000. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc Natl Acad Sci USA 97, 6138-6143. https://doi.org/10.1073/pnas.110126897
  36. Lopez-Munoz, F., Bhatara, V. S., Alamo, C. and Cuenca, E. 2004. Historical approach to reserpine discovery and its introduction in psychiatry. Actas Esp Psiquiatr 32, 387-395.
  37. Luo, W. J., Wang, H., Li, H., Kim, B. S., Shah, S., Lee, H. J., Thinakaran, G., Kim, T. W., Yu, G. and Xu, H. 2003. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem 278, 7850-7854. https://doi.org/10.1074/jbc.C200648200
  38. Mattson, M. P., Cheng, B., Davis, D., Bryant, K., Lieberburg, I. and Rydel, R. E. 1992. ${\beta}$-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neuro Sci 12, 376-389.
  39. Perini, G., Della-Bianca, V., Politi, V., Della, V. G., Dal-Pra, I., Rossi, F. and Armato, U. 2002. Role of p75 neurotrophin receptor in the neurotoxicity by ${\beta}$-amyloid peptides and synergistic effect of inflammatory cytokines. J Exp Med 195, 907-918. https://doi.org/10.1084/jem.20011797
  40. Pike, C. J., Burdick, D., Walencewicz, A. J., Glabe, C. G. and Cotman, C. W. 1993. Neurodegeneration induced by ${\beta}$-amyloid peptides in vitro: the role of peptide assembly state. J Neuro Sci 13, 1676-1687.
  41. Prajapati, K. D., Sharma, S. S. and Roy, N. 2010. Upregulation of albumin expression in focal ischemic rat brain. Brain Res 1327, 118-124. https://doi.org/10.1016/j.brainres.2010.02.063
  42. Rizarry, M., McNamara, M., Fedorchack, K., Hsiao, K. and Hyman, B. 1997. APPsw transgenic mice develop age-related Ab deposits and neurophil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neuro 56, 965-973. https://doi.org/10.1097/00005072-199709000-00002
  43. Russo, C., Dolcini, V., Salis, S., Venezia, V., Zambrano, N., Russo, T. and Schettini, G. 2002. Signal transduction through tyrosine-phosphorylated C-terminal fragments of amyloid precursor protein via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain. J Biol Chem 277, 35282-35288. https://doi.org/10.1074/jbc.M110785200
  44. Saharia, K., Arya, U., Kumar, R., Sahu, R., Das, C. K., Gupta, K., Dwivedi, H. and Subramaniam, J. R. 2012. Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent A${\beta}$ proteotoxicity in Caenorhabditis elegans. Exp Gerontol 47, 188-197. https://doi.org/10.1016/j.exger.2011.12.006
  45. Salehi, A., Delcroix, J. D. and Swaab, D. F. 2004. Alzheimer's disease and NGF signaling. J Neural Transm 111, 323-345. https://doi.org/10.1007/s00702-003-0091-x
  46. Shearman, M. S., Ragan, C. I. and Iversen, L. 1994. Inhibition of PC12 cell redox activity is a specific, early indicator of the mechanism of ${\beta}$-amyloid-mediated cell death. Proc Natl Acad Sci USA 91, 1470-1474. https://doi.org/10.1073/pnas.91.4.1470
  47. Slotkin, T. A. and Edwards, K. 1973. Effects of reserpine on the content and properties of rat adrenal medullary storage vesicles. Biochem Pharmacol 22, 549-560. https://doi.org/10.1016/0006-2952(73)90368-7
  48. Steiner, H., Winkler, E., Edbauer, D., Prokop, S., Basset, G., Yamasaki, A., Kostka, M. and Haass, C. 2002. PEN-2 is an integral component of the ${\gamma}$-secretase complex required for coordinated expression of presenilin and nicastrin. J Biol Chem 277, 39062-39065. https://doi.org/10.1074/jbc.C200469200
  49. Susen, K. and Blöchl, A. 2005. Low concetrations of aggregated ${\beta}$-amyloid induce neurite formation via the neurotrophin receptor p75. J Mol Med 83, 720-735. https://doi.org/10.1007/s00109-005-0671-3
  50. Takashima, A., Noguchi, K., Sato, K., Hoshino, T. and Imahori, K. 1993. Tau protein kinase I is essential for amyloid ${\beta}$-protein-induced neurotoxicity. Proc Natl Acad Sci USA 90, 7789-7793. https://doi.org/10.1073/pnas.90.16.7789
  51. Tarr, P. E., Roncarati, R., Pelicci, G., Pelicci, P. G. and D'Adamio, L. 2002. Tyrosine phosphorylation of the ${\beta}$-amyloid precursor protein cytoplasmic tail promotes interaction with Shc. J Biol Chem 277, 16798-16804. https://doi.org/10.1074/jbc.M110286200
  52. Thind, K. and Sabbagh, M. N. 2007. Pathological correlates of cognitive decline in Alzheimer's disease. Panminerva Med 49, 191-195.
  53. Tsui-Pierchala, B. A. and Ginty, D. D. 1999. Characterization of an NGF–P-TrkA retrograde-signaling complex and age-dependent regulation of TrkA phosphorylation in sympathetic neurons. J Neurosci 19, 8207-8218.
  54. Vakil, R. J. 1949. A clinical trial of Rauwolfia serpentina in essential hypertension. Br Heart J 11, 350-355. https://doi.org/10.1136/hrt.11.4.350
  55. Wasling, P., Daborg, J., Riebe, I., Andersson, M., Portelius, E., Blennow, K., Hanse, E. and Zetterberg, H. 2009. Synaptic retrogenesis and amyloid-beta in Alzheimer's disease. J Alzheimers Dis 16, 1-14.
  56. Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T. and Selkoe, D. J. 1999. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and ${\gamma}$-secretase activity. Nature 398, 513-517. https://doi.org/10.1038/19077
  57. Yankner, B. A., Duffy, L. K. and Kirschner, D. A. 1990. Neurotrophic and neurotoxic effects of amyloid ${\beta}$-protein: reversal by tachykinin neuropeptides. Science 250, 279-282. https://doi.org/10.1126/science.2218531
  58. Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., Tandon, A., Song, Y. Q., Rogaeva, E., Chen, F., Kawarai, T., Supala, A., Levesque, L., Yu, H., Yang, D. S., Holmes, E., Milman, P., Liang, Y., Zhang, D. M., Xu, D. H., Sato, C., Rogaev, E., Smith, M., Janus, C., Zhang, Y., Aebersold, R., Farrer, L. S., Sorbi, S., Bruni, A., Fraser, P. and St George-Hyslop, P. 2000. Nicastrin modulates presenilinmediated notch/glp-1 signal transduction and ${\beta}$APP processing. Nature 407, 48-54. https://doi.org/10.1038/35024009

Cited by

  1. Effect of Dropwort (Oenanthe javanica) Extracts on Memory Improvement in Alzheimer's Disease Animal Model, Tg2576 mice vol.47, pp.6, 2015, https://doi.org/10.9721/KJFST.2015.47.6.779
  2. Reserpine Improves Working Memory vol.06, pp.03, 2016, https://doi.org/10.4236/jbbs.2016.63012