Advertisement

Chemical Research in Chinese Universities

, Volume 35, Issue 2, pp 245–250 | Cite as

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

  • Jia Xu
  • Xiaoxuan Yu
  • Yue Zhang
  • Naizhang Liu
  • Shuwen GuanEmail author
  • Liping WangEmail author
Article
  • 10 Downloads

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 Aβ25—35 induced toxicity in SH-SY5Y cells, and significantly alleviated Aβ-induced paralysis and extended lifespan in Aβ1—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.

Keywords

Bifunctional peptide(BP) Aβ-Inhibitor Antioxidant Caenorhabditis elegans(C. elegans

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

40242_2019_8299_MOESM1_ESM.pdf (179 kb)
Supplementary material, approximately 180 KB.

References

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

Copyright information

© Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH 2019

Authors and Affiliations

  1. 1.School of Life SciencesJilin UniversityChangchunP. R. China
  2. 2.Engineering Laboratory for AIDS VaccineJilin UniversityChangchunP. R. China
  3. 3.Key Laboratory for Molecular Enzymology and Engineering, Ministry of EducationJilin UniverstiyChangchunP. R. China

Personalised recommendations