Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

β-Amyrin Ameliorates Alzheimer's Disease-Like Aberrant Synaptic Plasticity in the Mouse Hippocampus

  • Park, Hye Jin (Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University) ;
  • Kwon, Huiyoung (Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University) ;
  • Lee, Ji Hye (Division of Endocrinology, School of Medicine, Kyungpook National University) ;
  • Cho, Eunbi (Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University) ;
  • Lee, Young Choon (Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University) ;
  • Moon, Minho (Department of Biochemistry, College of Medicine, Konyang University) ;
  • Jun, Mira (Institute of Convergence Bio-Health, Dong-A University) ;
  • Kim, Dong Hyun (Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University) ;
  • Jung, Ji Wook (Department of Herbal Medicinal Pharmacology, College of Herbal Bio-industry, Daegu Haany University)
  • Received : 2019.02.08
  • Accepted : 2019.06.17
  • Published : 2019.12.30
Download PDF
⟨ Previous Next ⟩

Abstract

Alzheimer's disease (AD) is a progressive and most frequently diagnosed neurodegenerative disorder. However, there is still no drug preventing the progress of this disorder. β-Amyrin, an ingredient of the surface wax of tomato fruit and dandelion coffee, is previously reported to ameliorate memory impairment induced by cholinergic dysfunction. Therefore, we tested whether β-amyrin can prevent AD-like pathology. β-Amyrin blocked amyloid β (Aβ)-induced long-term potentiation (LTP) impairment in the hippocampal slices. Moreover, β-amyrin improved Aβ-induced suppression of phosphatidylinositol-3-kinase (PI3K)/Akt signaling. LY294002, a PI3K inhibitor, blocked the effect of β-amyrin on Aβ-induced LTP impairment. In in vivo experiments, we observed that β-amyrin ameliorated object recognition memory deficit in Aβ-injected AD mice model. Moreover, neurogenesis impairments induced by Aβ was improved by β-amyrin treatment. Taken together, β-amyrin might be a good candidate of treatment or supplement for AD patients.

Keywords

References

  1. Amani, M., Shokouhi, G. and Salari, A. A. (2019) Minocycline prevents the development of depression-like behavior and hippocampal inflammation in a rat model of Alzheimer's disease. Psychopharmacology (Berl.) 236, 1281-1292. https://doi.org/10.1007/s00213-018-5137-8
  2. Arbel-Ornath, M., Hudry, E., Boivin, J. R., Hashimoto, T., Takeda, S., Kuchibhotla, K. V., Hou, S., Lattarulo, C. R., Belcher, A. M., Shakerdge, N., Trujillo, P. B., Muzikansky, A., Betensky, R. A., Hyman, B. T. and Bacskai, B. J. (2017) Soluble oligomeric amyloid-beta induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. Mol. Neurodegener. 12, 27. https://doi.org/10.1186/s13024-017-0169-9
  3. Beurel, E., Grieco, S. F. and Jope, R. S. (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol. Ther. 148, 114-131. https://doi.org/10.1016/j.pharmthera.2014.11.016
  4. Birnbaum, J. H., Bali, J., Rajendran, L., Nitsch, R. M. and Tackenberg, C. (2015) Calcium flux-independent NMDA receptor activity is required for Abeta oligomer-induced synaptic loss. Cell Death Dis. 6, e1791. https://doi.org/10.1038/cddis.2015.160
  5. Chen, T. J., Wang, D. C. and Chen, S. S. (2009) Amyloid-beta interrupts the PI3K-Akt-mTOR signaling pathway that could be involved in brain-derived neurotrophic factor-induced Arc expression in rat cortical neurons. J. Neurosci. Res. 87, 2297-2307. https://doi.org/10.1002/jnr.22057
  6. Chicca, A., Marazzi, J. and Gertsch, J. (2012) The antinociceptive triterpene beta-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydro-lysis without directly targeting cannabinoid receptors. Br. J. Pharmacol. 167, 1596-1608. https://doi.org/10.1111/j.1476-5381.2012.02059.x
  7. da Silva, K. A., Paszcuk, A. F., Passos, G. F., Silva, E. S., Bento, A. F., Meotti, F. C. and Calixto, J. B. (2011) Activation of cannabinoid receptors by the pentacyclic triterpene alpha,beta-amyrin inhibits inflammatory and neuropathic persistent pain in mice. Pain 152, 1872-1887. https://doi.org/10.1016/j.pain.2011.04.005
  8. Dubois, B., Feldman, H. H., Jacova, C., Dekosky, S. T., Barberger-Gateau, P., Cummings, J., Delacourte, A., Galasko, D., Gauthier, S., Jicha, G., Meguro, K., O'Brien, J., Pasquier, F., Robert, P., Rossor, M., Salloway, S., Stern, Y., Visser, P. J. and Scheltens, P. (2007) Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 6, 734-746. https://doi.org/10.1016/S1474-4422(07)70178-3
  9. Ferretti, M. T., Allard, S., Partridge, V., Ducatenzeiler, A. and Cuello, A. C. (2012) Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J. Neuroinflammation 9, 62.
  10. Fu, A. K., Hung, K. W., Huang, H., Gu, S., Shen, Y., Cheng, E. Y., Ip, F. C., Huang, X., Fu, W. Y. and Ip, N. Y. (2014) Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 111, 9959-9964. https://doi.org/10.1073/pnas.1405803111
  11. Gregoire, C. A., Bonenfant, D., Le Nguyen, A., Aumont, A. and Fernandes, K. J. (2014) Untangling the influences of voluntary running, environmental complexity, social housing and stress on adult hippocampal neurogenesis. PLoS ONE 9, e86237. https://doi.org/10.1371/journal.pone.0086237
  12. Hardy, J. and Selkoe, D. J. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353-356. https://doi.org/10.1126/science.1072994
  13. Haughey, N. J., Nath, A., Chan, S. L., Borchard, A. C., Rao, M. S. and Mattson, M. P. (2002) Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J. Neurochem. 83, 1509-1524. https://doi.org/10.1046/j.1471-4159.2002.01267.x
  14. Ishii, M., Nakahara, T., Ikeuchi, S. and Nishimura, M. (2015) beta-Amyrin induces angiogenesis in vascular endothelial cells through the Akt/endothelial nitric oxide synthase signaling pathway. Biochem. Biophys. Res. Commun. 467, 676-682. https://doi.org/10.1016/j.bbrc.2015.10.085
  15. Jeon, S. J., Park, H. J., Gao, Q., Lee, H. E., Park, S. J., Hong, E., Jang, D. S., Shin, C. Y., Cheong, J. H. and Ryu, J. H. (2015) Positive effects of beta-amyrin on pentobarbital-induced sleep in mice via GABAergic neurotransmitter system. Behav. Brain Res. 291, 232-236. https://doi.org/10.1016/j.bbr.2015.05.005
  16. Jiang, Y., Liu, Y., Zhu, C., Ma, X., Ma, L., Zhou, L., Huang, Q., Cen, L., Pi, R. and Chen, X. (2015) Minocycline enhances hippocampal memory, neuroplasticity and synapse-associated proteins in aged C57 BL/6 mice. Neurobiol. Learn. Mem. 121, 20-29. https://doi.org/10.1016/j.nlm.2015.03.003
  17. Jo, J., Whitcomb, D. J., Olsen, K. M., Kerrigan, T. L., Lo, S. C., Bru-Mercier, G., Dickinson, B., Scullion, S., Sheng, M., Collingridge, G. and Cho, K. (2011) Abeta(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta. Nat. Neurosci. 14, 545-547. https://doi.org/10.1038/nn.2785
  18. Kim, H. Y., Lee, D. K., Chung, B. R., Kim, H. V. and Kim, Y. (2016) Intracerebroventricular injection of amyloid-beta peptides in normal mice to acutely induce alzheimer-like cognitive deficits. J. Vis. Exp. (109), e53308.
  19. Kitagishi, Y., Nakanishi, A., Ogura, Y. and Matsuda, S. (2014) Dietary regulation of PI3K/AKT/GSK-3beta pathway in Alzheimer's disease. Alzheimers Res. Ther. 6, 35. https://doi.org/10.1186/alzrt265
  20. Krishnan, K., Mathew, L. E., Vijayalakshmi, N. R. and Helen, A. (2014) Anti-inflammatory potential of beta-amyrin, a triterpenoid isolated from Costus igneus. Inflammopharmacology 22, 373-385. https://doi.org/10.1007/s10787-014-0218-8
  21. Ma, J., Gao, Y., Jiang, L., Chao, F. L., Huang, W., Zhou, C. N., Tang, W., Zhang, L., Huang, C. X., Zhang, Y., Luo, Y. M., Xiao, Q., Yu, H. R., Jiang, R. and Tang, Y. (2017) Fluoxetine attenuates the impairment of spatial learning ability and prevents neuron loss in middleaged APPswe/PSEN1dE9 double transgenic Alzheimer’s disease mice. Oncotarget 8, 27676-27692. https://doi.org/10.18632/oncotarget.15398
  22. Maurya, R., Srivastava, A., Shah, P., Siddiqi, M. I., Rajendran, S. M., Puri, A. and Yadav, P. P. (2012) beta-Amyrin acetate and betaamyrin palmitate as antidyslipidemic agents from Wrightia tomentosa leaves. Phytomedicine 19, 682-685. https://doi.org/10.1016/j.phymed.2012.03.013
  23. Mu, Y. and Gage, F. H. (2011) Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol. Neurodegener. 6, 85. https://doi.org/10.1186/1750-1326-6-85
  24. Nabavi, S., Fox, R., Proulx, C. D., Lin, J. Y., Tsien, R. Y. and Malinow, R. (2014) Engineering a memory with LTD and LTP. Nature 511, 348-352. https://doi.org/10.1038/nature13294
  25. Nair, A. B. and Jacob, S. (2016) A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27-31. https://doi.org/10.4103/0976-0105.177703
  26. Nair, S. A., Sabulal, B., Radhika, J., Arunkumar, R. and Subramoniam, A. (2014) Promising anti-diabetes mellitus activity in rats of betaamyrin palmitate isolated from Hemidesmus indicus roots. Eur. J. Pharmacol. 734, 77-82. https://doi.org/10.1016/j.ejphar.2014.03.050
  27. Noble, W., Garwood, C., Stephenson, J., Kinsey, A. M., Hanger, D. P. and Anderton, B. H. (2009) Minocycline reduces the development of abnormal tau species in models of Alzheimer's disease. FASEB J. 23, 739-750. https://doi.org/10.1096/fj.08-113795
  28. Okoye, N. N., Ajaghaku, D. L., Okeke, H. N., Ilodigwe, E. E., Nworu, C. S. and Okoye, F. B. (2014) beta-Amyrin and alpha-amyrin acetate isolated from the stem bark of Alstonia boonei display profound anti-inflammatory activity. Pharm. Biol. 52, 1478-1486. https://doi.org/10.3109/13880209.2014.898078
  29. Park, S. J., Ahn, Y. J., Oh, S. R., Lee, Y., Kwon, G., Woo, H., Lee, H. E., Jang, D. S., Jung, J. W. and Ryu, J. H. (2014) Amyrin attenuates scopolamine-induced cognitive impairment in mice. Biol. Pharm. Bull. 37, 1207-1213. https://doi.org/10.1248/bpb.b14-00113
  30. Penn, A. C., Zhang, C. L., Georges, F., Royer, L., Breillat, C., Hosy, E., Petersen, J. D., Humeau, Y. and Choquet, D. (2017) Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors. Nature 549, 384-388. https://doi.org/10.1038/nature23658
  31. Reddy, P. H. (2013) Amyloid beta-induced glycogen synthase kinase 3beta phosphorylated VDAC1 in Alzheimer's disease: implications for synaptic dysfunction and neuronal damage. Biochim. Biophys. Acta 1832, 1913-1921. https://doi.org/10.1016/j.bbadis.2013.06.012
  32. Rodriguez, J. J., Jones, V. C., Tabuchi, M., Allan, S. M., Knight, E. M., LaFerla, F. M., Oddo, S. and Verkhratsky, A. (2008) Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS ONE 3, e2935. https://doi.org/10.1371/journal.pone.0002935
  33. Rodriguez, J. J., Noristani, H. N., Olabarria, M., Fletcher, J., Somerville, T. D., Yeh, C. Y. and Verkhratsky, A. (2011) Voluntary running and environmental enrichment restores impaired hippocampal neurogenesis in a triple transgenic mouse model of Alzheimer's disease. Curr. Alzheimer Res. 8, 707-717. https://doi.org/10.2174/156720511797633214
  34. Rodriguez, J. J. and Verkhratsky, A. (2011) Neurogenesis in Alzheimer's disease. J. Anat. 219, 78-89. https://doi.org/10.1111/j.1469-7580.2011.01343.x
  35. Santos, F. A., Frota, J. T., Arruda, B. R., de Melo, T. S., da Silva, A. A., Brito, G. A., Chaves, M. H. and Rao, V. S. (2012) Antihyperglycemic and hypolipidemic effects of alpha, beta-amyrin, a triterpenoid mixture from Protium heptaphyllum in mice. Lipids Health Dis. 11, 98. https://doi.org/10.1186/1476-511X-11-98
  36. Selkoe, D. J. (1991) The molecular pathology of Alzheimer’s disease. Neuron 6, 487-498. https://doi.org/10.1016/0896-6273(91)90052-2
  37. Shimshek, D. R., Bus, T., Schupp, B., Jensen, V., Marx, V., Layer, L. E., Kohr, G. and Sprengel, R. (2017) Different forms of AMPA receptor mediated LTP and their correlation to the spatial working memory formation. Front. Mol. Neurosci. 10, 214. https://doi.org/10.3389/fnmol.2017.00214
  38. Stein, E. S., Itsekson-Hayosh, Z., Aronovich, A., Reisner, Y., Bushi, D., Pick, C. G., Tanne, D., Chapman, J., Vlachos, A. and Maggio, N. (2015) Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke. Sci. Rep. 5, 7912. https://doi.org/10.1038/srep07912
  39. Szakiel, A., Paczkowski, C., Pensec, F. and Bertsch, C. (2012) Fruit cuticular waxes as a source of biologically active triterpenoids. Phytochem. Rev. 11, 263-284. https://doi.org/10.1007/s11101-012-9241-9
  40. Tapia-Rojas, C., Aranguiz, F., Varela-Nallar, L. and Inestrosa, N. C. (2016) Voluntary running attenuates memory loss, decreases neuropathological changes and induces neurogenesis in a mouse model of Alzheimer's disease. Brain Pathol. 26, 62-74. https://doi.org/10.1111/bpa.12255
  41. Thirupathi, A., Silveira, P. C., Nesi, R. T. and Pinho, R. A. (2017) beta-Amyrin, a pentacyclic triterpene, exhibits anti-fibrotic, anti-inflammatory, and anti-apoptotic effects on dimethyl nitrosamine-induced hepatic fibrosis in male rats. Hum. Exp. Toxicol. 36, 113-122. https://doi.org/10.1177/0960327116638727
  42. Tiwari, S. K., Seth, B., Agarwal, S., Yadav, A., Karmakar, M., Gupta, S. K., Choubey, V., Sharma, A. and Chaturvedi, R. K. (2015) Ethosuximide induces hippocampal neurogenesis and reverses cognitive deficits in an amyloid-beta toxin-induced alzheimer rat model via the phosphatidylinositol 3-kinase (PI3K)/Akt/Wnt/beta-catenin pathway. J. Biol. Chem. 290, 28540-28558. https://doi.org/10.1074/jbc.M115.652586
  43. Tozzi, A., Sclip, A., Tantucci, M., de Iure, A., Ghiglieri, V., Costa, C., Di Filippo, M., Borsello, T. and Calabresi, P. (2015) Region-and agedependent reductions of hippocampal long-term potentiation and NMDA to AMPA ratio in a genetic model of Alzheimer's disease. Neurobiol. Aging 36, 123-133. https://doi.org/10.1016/j.neurobiolaging.2014.07.002
  44. Viola, K. L. and Klein, W. L. (2015) Amyloid beta oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 129, 183-206. https://doi.org/10.1007/s00401-015-1386-3
  45. Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J. and Selkoe, D. J. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539. https://doi.org/10.1038/416535a
  46. Yan, R., Fan, Q., Zhou, J. and Vassar, R. (2016) Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer's disease. Neurosci. Biobehav. Rev. 65, 326-340. https://doi.org/10.1016/j.neubiorev.2016.03.025
  47. Yi, J. H., Baek, S. J., Heo, S., Park, H. J., Kwon, H., Lee, S., Jung, J., Park, S. J., Kim, B. C., Lee, Y. C., Ryu, J. H. and Kim, D. H. (2018) Direct pharmacological Akt activation rescues Alzheimer’s disease like memory impairments and aberrant synaptic plasticity. Neuropharmacology 128, 282-292. https://doi.org/10.1016/j.neuropharm.2017.10.028
  48. Zhu, G., Li, J., He, L., Wang, X. and Hong, X. (2015) MPTP-induced changes in hippocampal synaptic plasticity and memory are prevented by memantine through the BDNF-TrkB pathway. Br. J. Pharmacol. 172, 2354-2368. https://doi.org/10.1111/bph.13061
  49. Ziabreva, I., Perry, E., Perry, R., Minger, S. L., Ekonomou, A., Przyborski, S. and Ballard, C. (2006) Altered neurogenesis in Alzheimer's disease. J. Psychosom. Res. 61, 311-316. https://doi.org/10.1016/j.jpsychores.2006.07.017

Cited by

  1. On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence vol.39, pp.6, 2021, https://doi.org/10.1007/s12640-021-00424-z
  2. Updates and advances on pharmacological properties of Taraxacum mongolicum Hand.-Mazz and its potential applications vol.373, pp.no.pa, 2020, https://doi.org/10.1016/j.foodchem.2021.131380