Extending Lifespan of Alzheimer's Mode Nematode CL4176 Using a Novel Bifunctional Peptide with Inhibition of β-Amyloid Aggregation and Anti-oxidation

doi:10.1007/s40242-019-8299-y

Abstract

Abstract: Alzheimer's disease(AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid peptide(Aβ) in the brain tissues, and an imbalance in the oxidant-antioxidant system. Compounds with antioxidant activity and the ability to inhibit Aβ aggregation therefore potentially treat AD. In this study, we designed an iron-porphyrin containing bifunctional peptide(BP, Deuterohemin-AlaHisThrValGluLysLeuProPhePheAsp) based on natural microperoxidase-11(MP-11) and typical β-sheet breaker LPFFD(iAβ5p). This BP substantially reduced the aggregation of Aβ and caused oligomer disassembly, by binding Aβ with affinity constant of 9.07 μmol/L. Furthermore, it showed a neuroprotective effect on Aβ_25-35 induced toxicity in SH-SY5Y cells, and significantly alleviated Aβ-induced paralysis and extended lifespan in Aβ_1-42 transgenic C. elegans(CL4176). It also showed a potent peroxidase activity of 20.8 U/mg, and scavenged free radicals both in vitro and in vivo. In addition, BP up-regulated the levels of hsp16.2, hsp16.41, and hsp12.6 mRNAs to 183.26%, 160.16%, and 162.64% respectively, and down-regulated that of hsp70 to 36.76% in C. elegans. Taken together, the synthetic BP inhibited Aβ aggregation and showed antioxidant activity, indicating the therapeutic potential of novel peptide drugs against AD.

Key words: Bifunctional peptide(BP), Aβ-Inhibitor, Antioxidant, Caenorhabditis elegans(C. elegans)

XU Jia, YU Xiaoxuan, ZHANG Yue, LIU Naizhang, GUAN Shuwen, WANG Liping. Extending Lifespan of Alzheimer's Mode Nematode CL4176 Using a Novel Bifunctional Peptide with Inhibition of β-Amyloid Aggregation and Anti-oxidation[J]. Chemical Research in Chinese Universities, 2019, 35(2): 245-250.

References

[1] Querfurth H. W., Laferla F. M., New England Journal of Medicine, 2010, 362(4), 329
[2] Masters C. L., Simms G., Weinman N. A., Multhaup G., Mcdonald B. L., Beyreuther K., Proceedings of the National Academy of Sciences of the United States of America, 1985, 82(12), 4245
[3] Priller C., Bauer T., Mitteregger G., Krebs B., Kretzschmar H. A., Herms J. Journal of Neuroscience, 2006, 2(3), 77
[4] Turner P. R., O'Connor K., Tate W. P., Abraham W. C., Progress in Neurobiology, 2003, 70(1), 1
[5] Wenk G. L., Journal of Clinical Psychiatry, 2006, 64(3), 7
[6] Haass C., Selkoe D. J., Nature Reviews Molecular Cell Biology, 2007, 8(2), 101
[7] Ohnishi S., Takano K., Cellular & Molecular Life Sciences, 2004, 61(5), 511
[8] Lott I. T., Head E., Neurobiology of Aging, 2005, 26(3), 383
[9] Hardy J. A., Higgins G. A., Science, 1992, 256(5054), 184
[10] Hardy J., Selkoe D. J., Science, 2002, 297(5580), 353
[11] Joseph T., Peter T., Cell, 1993, 73(6), 1055
[12] Opar A., Nature Reviews Drug Discovery, 2008, 7(9), 717
[13] Markesbery W. R., Free Radical Biology & Medicine, 1997, 23(1), 134
[14] Dumont M., Beal M. F., Free Radical Biology & Medicine, 2011, 51(5), 1014
[15] Awasthi M., Singh S., Pandey V. P., Dwivedi U. N., Medicinal Chemistry Research, 2018, 27(4), 1
[16] Bastianetto S., Zheng W., Quirion R., British Journal of Pharmaco-logy, 2010, 131(4), 711
[17] Mao F., Yan J., Li J., Jia X., Miao H., Sun Y., Huang L., Li X., Organic & Biomolecular Chemistry, 2014, 12(31), 5936
[18] Ringman J. M., Frautschy S. A., Teng E., Begum A. N., Bardens J., Beigi M., Gylys K. H., Badmaev V., Heath D. D., Apostolova L. G., Poter V., Vanek Z., Marshall G. A., Hellemann G., Alzheimers Research & Therapy, 2012, 4(5), 43
[19] Liu Z. J., Li Z. H., Lei L., Tang W. X., Yu W., Dong M. R., Cheng X., Front Pharmacol., 2016, 7, 261
[20] Wang Q., Sun A. Y., Simonyi A., Jensen M. D., Shelat P. B., Rottinghaus G. E., MacDonald R. S., Miller K. D., Lubahn D. E., Weisman G. A., Sun G. Y., Journal of Neuroscience Research, 2010, 82(1),138
[21] Zhang Z., Ma H., Wang X., Zhao Z., Zhang Y., Zhao B., Guo Y., Xu L., RSC Advances, 2016, 6, 56851
[22] Howes M. J. R., Perry N. S. L., Houghton P. J., Phytotherapy Research, 2003, 17(1), 1
[23] Rao R. V., Descamps O., John V., Bredesen D. E., Alzheimers Research & Therapy, 2012, 4(3), 1
[24] Russo P., Frustaci A., Del B. A., Fini M., Cesario A., Current Medicinal Chemistry, 2013, 20(13), 1686
[25] Atamna H., Boyle K., Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(9), 3381
[26] Ghosh C., Mukherjee S., Seal M., Dey S. G., Inorganic Chemistry, 2016, 55(4), 1748
[27] Chiziane E., Telemann H., Krueger M., Adler J., Arnhold J., Alia A., Flemmig J., Journal of Alzheimers Disease, 2018, 61(3), 963
[28] Laszlo J. A., Compton D. L., Journal of Molecular Catalysis B Enzymatic, 2002, 18(1), 109
[29] Wang L. P., Liu Y. L., Yang H., Li W., Chem. J. Chinese Universities, 2004, 25(11), 2171
[30] Soto C., Sigurdsson E. M., Morelli L., Kumar R. A., Castaño E. M., Frangione B., Nature Medicine, 1998, 4(7), 822
[31] Viet M. H., Ngo S. T., Lam N. S., Li M. S., Journal of Physical Chemistry B, 2011, 115(22), 7433
[32] Sinopoli A., Giuffrida A., Tomasello M. F., Giuffrida M. L., Leone M., Attanasio F., Caraci F., Bona P. D., Naletova I., Saviano M., Chembiochem:European Journal of Chemical Biology, 2016, 17(16), 1541
[33] Xiong N., Dong X. Y., Zheng J., Liu F. F., Sun Y., ACS Appl. Mater. Interfaces, 2015, 7(10), 5650
[34] Liu Y. L., Guo L., Roeske R., Luo G. M., Li W., Acta Scientiarium Naturalium Universitatis Jilinensis, 2001, 25(11), 2171
[35] Lei L., Zhang G., Li P., Zhang Y., Guo Y., Zhang W., Zhang W., Hu B., Wang L., Chemico-biological Interactions, 2014, 220, 64
[36] Fu L., Li Y., Hu Y., Zheng Y., Yu B., Zhang H., Wu J., Wu H., Yu X., Kong W., Scientific Reports, 2017, 7, 41041
[37] Zhang Q., Liu J., Hu X., Wang W., Yuan Z., ACS Macro Letters, 2015, 4(4), 339
[38] Fu L., Sun Y., Guo Y., Chen Y., Yu B., Zhang H., Wu J., Yu X., Kong W., Wu H., Journal of Peptide Science, 2017, 23(3), 245
[39] Shah N. B., Duncan T. M., Journal of Visualized Experiments Jove, 2014, 18(84), 51383
[40] Hara K., Someya T., Sano K., Sagane Y., Watanabe T., Rgs W., Data in Brie, 2018, 17, 870
[41] Zhou J. B., Zheng Y. L., Zeng Y. X., Wang J. W., Pei Z., Pang J. Y., European Journal of Medicinal Chemistry, 2018, 148, 63
[42] Kampkötter A., Nkwonkam C. G., Zurawski R. F., Timpel C, Chovolou Y., Wätjen W., Kahl R., Toxicology, 2007, 234(1), 113
[43] Li Y., Guan S., Liu C, Chen X., Zhu Y., Xie Y., Wang J., Ji X., Li L, Li Z., Zhang Y., Zeng X., Li M., International Journal of Biological Macromolecules, 2018, 113, 991
[44] Xu J., Guo Y., Sui T., Wang Q., Yue Z., Zhang R., Wang M., Guan S., Wang L., Free Radical Research, 2017, 51(5), 1