Browse > Article

Amelioration of Cognitive Dysfunction in APP/PS1 Double Transgenic Mice by Long-Term Treatment of 4-O-Methylhonokiol  

Jung, Yu-Yeon (College of Pharmacy, Chungbuk National University)
Lee, Young-Jung (School of Equine industries, Cheju Halla University)
Choi, Dong-Young (College of Pharmacy, Yeungnam University)
Hong, Jin Tae (College of Pharmacy, Chungbuk National University)
Publication Information
Biomolecules & Therapeutics / v.22, no.3, 2014 , pp. 232-238 More about this Journal
Alzheimer's disease (AD) is the most common neurodegenerative disease without known ways to cure. A key neuropathologic manifestation of the disease is extracellular deposition of beta-amyloid peptide (Ab). Specific mechanisms underlying the development of the disease have not yet been fully understood. In this study, we investigated effects of 4-O-methylhonokiol on memory dysfunction in APP/PS1 double transgenic mice. 4-O-methylhonokiol (1 mg/kg for 3 month) significantly reduced deficit in learning and memory of the transgenic mice, as determined by the Morris water maze test and step-through passive avoidance test. Our biochemical analysis suggested that 4-O-methylhonokiol ameliorated $A{\beta}$ accumulation in the cortex and hippocampus via reduction in beta-site APP-cleaving enzyme 1 expression. In addition, 4-O-methylhonokiol attenuated lipid peroxidation and elevated glutathione peroxidase activity in the double transgenic mice brains. Thus, suppressive effects of 4-O-methylhonokiol on $A{\beta}$ generation and oxidative stress in the brains of transgenic mice may be responsible for the enhancement in cognitive function. These results suggest that the natural compound has potential to intervene memory deficit and progressive neurodegeneration in AD patients.
Alzheimer's disease; 4-O-methylhonokiol; APP/PS1 double transgenic; Antioxidant; Beta-site APP-cleaving enzyme;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Sastre, M., Walter, J. and Gentleman, S. M. (2008) Interactions between APP secretases and inflammatory mediators. J. Neuroinflammation 5, 25.   DOI   ScienceOn
2 Lee, Y. J., Choi, D. Y., Choi, I. S., Kim, K. H., Kim, Y. H., Kim, H. M., Lee, K., Cho, W. G., Jung, J. K., Han, S. B., Han, J. Y., Nam, S. Y., Yun, Y. W., Jeong, J. H., Oh, K. W. and Hong, J. T. (2012a) Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. J. Neuroinflammation 9, 35.   DOI
3 Lee, Y. J., Choi, D. Y., Lee, Y. K., Lee, Y. M., Han, S. B., Kim, Y. H., Kim, K. H., Nam, S. Y., Lee, B. J., Kang, J. K., Yun, Y. W., Oh, K. W. and Hong, J. T. (2012b) 4-O-methylhonokiol prevents memory impairment in the Tg2576 transgenic mice model of Alzheimer's disease via regulation of beta-secretase activity. J. Alzheimers Dis. 29, 677-690.
4 Lee, Y. J., Choi, D. Y., Yun, Y. P., Han, S. B., Kim, H. M., Lee, K., Choi, S. H., Yang, M. P., Jeon, H. S., Jeong, J. H., Oh, K. W. and Hong, J. T. (2013) Ethanol extract of Magnolia officinalis prevents lipopolysaccharide- induced memory deficiency via its antineuroinflammatory and antiamyloidogenic effects. Phytother. Res. 27, 438-447.   DOI   ScienceOn
5 Lee, Y. J., Choi, I. S., Park, M. H., Lee, Y. M., Song, J. K., Kim, Y. H., Kim, K. H., Hwang, D. Y., Jeong, J. H., Yun, Y. P., Oh, K. W., Jung, J. K., Han, S. B. and Hong, J. T. (2011) 4-O-Methylhonokiol attenuates memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the ERK pathway. Free Radic. Biol. Med. 50, 66-77.   DOI
6 Fukui, H., Diaz, F., Garcia, S. and Moraes, C. T. (2007) Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 104, 14163-14168.   DOI
7 Gertsch, J. and Anavi-Goffer, S. (2012) Methylhonokiol attenuates neuroinflammation: a role for cannabinoid receptors? J. Neuroinflamm. 9, 135.   DOI
8 Guglielmotto, M., Giliberto, L., Tamagno, E. and Tabaton, M. (2010) Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors. Front. Aging Neurosci. 2, 3.
9 Hardy, J. and Allsop, D. (1991) Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 12, 383-388.   DOI   ScienceOn
10 Herreman, A., Serneels, L., Annaert, W., Collen, D., Schoonjans, L. and De Strooper, B. (2000) Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell Biol. 2, 461-462.   DOI   ScienceOn
11 Ho, K. Y., Tsai, C. C., Chen, C. P., Huang, J. S. and Lin, C. C. (2001) Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis. Phytother. Res. 15, 139-141.   DOI   ScienceOn
12 Holsinger, R. M., McLean, C. A., Beyreuther, K., Masters, C. L. and Evin, G. (2002) Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann. Neurol. 51, 783-786.   DOI   ScienceOn
13 Bourne, K. Z., Ferrari, D. C., Lange-Dohna, C., Rossner, S., Wood, T. G. and Perez-Polo, J. R. (2007) Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides. J. Neurosci. Res. 85, 1194-1204.   DOI
14 Cole, S. L. and Vassar, R. (2008) The role of amyloid precursor protein processing by BACE1, the beta-secretase, in Alzheimer disease pathophysiology. J. Biol. Chem. 283, 29621-29625.   DOI
15 Chen, C. H., Zhou, W., Liu, S., Deng, Y., Cai, F., Tone, M., Tone, Y., Tong, Y. and Song, W. (2012) Increased NF-kappaB signalling up-regulates BACE1 expressionand its therapeutic potential in Alzheimer's disease. Int. J. Neuropsychopharmacol. 15, 77-90   DOI
16 Choi, D. Y., Lee, J. W., Lin, G., Lee, Y. K., Lee, Y. H., Choi, I. S., Han, S. B., Jung, J. K., Kim, Y. H., Kim, K. H., Oh, K. W., Hong, J. T. and Lee, M. S. (2012b) Obovatol attenuates LPS-induced memory impairments in mice via inhibition of NF-kappaB signaling pathway. Neurochem. Int. 60, 68-77.   DOI   ScienceOn
17 Choi, I. S., Lee, Y. J., Choi, D. Y., Lee, Y. K., Lee, Y. H., Kim, K. H., Kim, Y. H., Jeon, Y. H., Kim, E. H., Han, S. B., Jung, J. K., Yun, Y. P., Oh, K. W., Hwang, D. Y. and Hong, J. T. (2011) 4-O-methylhonokiol attenuated memory impairment through modulation of oxidative damage of enzymes involving amyloid-beta generation and accumulation in a mouse model of Alzheimer's disease. J. Alzheimers Dis. 27, 127-141.
18 De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K. and Van Leuven, F. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387-390.   DOI   ScienceOn
19 Ashton, J. C. and Glass, M. (2007) The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr. Neuropharmacol. 5, 73-80.   DOI   ScienceOn
20 Borchelt, D. R., Ratovitski, T., van Lare, J., Lee, M. K., Gonzales, V., Jenkins, N. A., Copeland, N. G., Price, D. L. and Sisodia, S. S. (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939-945.   DOI   ScienceOn
21 Schuehly, W., Paredes, J. M., Kleyer, J., Huefner, A., Anavi-Goffer, S., Raduner, S., Altmann, K. H. and Gertsch, J. (2011) Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists. Chem. Biol. 18, 1053-1064.   DOI
22 Seo, J. J., Lee, S. H., Lee, Y. S., Kwon, B. M., Ma, Y., Hwang, B. Y., Hong, J. T. and Oh, K. W. (2007) Anxiolytic-like effects of obovatol isolated from Magnolia obovata: involvement of GABA/benzodiazepine receptors complex. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 1363-1369.
23 Tamagno, E., Bardini, P., Obbili, A., Vitali, A., Borghi, R., Zaccheo, D., Prozato, M. A., Danni, O., Smith, M. A., Perry, G. and Tabaton, M. (2002) Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol. Dis. 10, 279-288.   DOI   ScienceOn
24 McGowan, E., Sanders, S., Iwatsubo, T., Takeuchi, A., Saido, T., Zehr, C., Yu, X., Uljon, S., Wang, R., Mann, D., Dickson, D. and Duff, K. (1999) Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol. Dis. 6, 231-244.   DOI   ScienceOn
25 Yang, H., Zhuo, J. M., Chu, J., Chinnici, C. and Pratico, D. (2010) Amelioration of the Alzheimer's disease phenotype by absence of 12/15-lipoxygenase. Biol. Psychiatry 68, 922-929.   DOI
26 Lee, Y. K., Choi, I. S., Kim, Y. H., Kim, K. H., Nam, S. Y., Yun, Y. W., Lee, M. S., Oh, K. W. and Hong, J. T. (2009) Neurite outgrowth effect of 4-O-methyl honokiol by induction of neurotrophic factors through ERK activation. Neurochem. Res. 34, 2251-2260.   DOI   ScienceOn
27 Matsui, N., Takahashi, K., Takeichi, M., Kuroshita, T., Noguchi, K., Yamazaki, K., Tagashira, H., Tsutsui, K., Okada, H., Kido, Y., Yasui, Y., Fukuishi, N., Fukuyama, Y. and Akagi, M. (2009) Magnolol and honokiol prevent learning and memory impairment and cholinergic deficit in SAMP8 mice. Brain Res. 1305, 108-117.   DOI
28 Octave, J. N., Essalmani, R., Tasiaux, B., Menager, J., Czech, C. and Mercken, L. (2000) The role of presenilin-1 in the gamma-secretase cleavage of the amyloid precursor protein of Alzheimer's disease. J. Biol. Chem. 275, 1525-1528.   DOI   ScienceOn
29 Price, D. L. and Sisodia, S. S. (1998) Mutant genes in familial Alzheimer's disease and transgenic models. Ann. Rev. Neurosci. 21, 479-505.   DOI   ScienceOn
30 Sambamurti, K., Kinsey, R., Maloney, B., Ge, Y. W. and Lahiri, D. K. (2004) Gene structure and organization of the human beta-secretase (BACE) promoter. FASEB J. 18, 1034-1036.
31 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.   DOI   ScienceOn
32 Choi, D. Y., Lee, J. W., Lin, G., Lee, Y. J., Ban, J. O., Lee, Y. H., Choi, I. S., Han, S. B., Jung, J. K., Lee, W. S., Lee, S. H., Kwon, B. M., Oh, K. W. and Hong, J. T. (2012a) Obovatol improves cognitive functions in animal models for Alzheimer's disease. J. Neurochem. 120, 1048-1059
33 Ai, J., Sun, L. H., Che, H., Zhang, R., Zhang, T. Z., Wu, W. C., Su, X. L., Chen, X., Yang, G., Li, K., Wang, N., Ban, T., Bao, Y. N., Guo, F., Niu, H. F., Zhu, Y. L., Zhu, X. Y., Zhao, S. G. and Yang, B. F. (2013) MicroRNA-195 protects against dementia induced by chronic brain hypoperfusion via its anti-amyloidogenic effect in rats. J. Neurosci. 33, 3989-4001.   DOI
34 Kimberly, W. T., Xia, W., Rahmati, T., Wolfe, M. S. and Selkoe, D. J. (2000) The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J. Biol. Chem. 275, 3173-3178.   DOI