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[Gly14]-Humanin Protects Against Amyloid β Peptide-Induced Impairment of Spatial Learning and Memory in Rats

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Abstract

Alzheimer disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and the accumulation of senile plaques in the brain. Amyloid β protein (Aβ) in the plaques is thought to be responsible for the memory loss in AD patients. [Gly14]-humanin (HNG), a derivative of humanin (HN), has much stronger neuroprotective effects than natural HN in vitro. However, clarification of the Aβ active center and the neuroprotective mechanism of HN still need in vivo evidence. The present study first compared the in vivo biological effects of three Aβ fragments (1–42, 31–35, and 35–31) on spatial memory in rats, and investigated the neuroprotective effects and molecular mechanisms of HNG. The results showed that intrahippocampal injection of Aβ1–42 and Aβ31–35 almost equally impaired spatial learning and memory, but the reversed sequence Aβ35–31 did not have any effect; a high dose of Aβ31–35 (20 nmol) produced a more detrimental response than a low dose (2 nmol); Aβ31–35 injection also disrupted gene and protein expression in the hippocampus, with up-regulation of caspase3 and down-regulation of STAT3; pretreatment with HNG not only protected spatial memory but also rescued STAT3 from Aβ-induced disruption; and the neuroprotective effects of HNG were effectively counteracted by genistein, a specific tyrosine kinase inhibitor. These results clearly show that sequence 31–35 in Aβ is the shortest active center responsible for the neurotoxicity of Aβ from molecule to behavior; and HNG protects spatial learning and memory in rats against Aβ-induced insults; and probably involves the activation of tyrosine kinases and subsequent beneficial modulation of STAT3 and caspase3.

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References

  1. Tanzi RE, Bertram L. Alzheimer’s disease: The latest suspect. Nature 2008, 454: 706–708.

    Article  CAS  PubMed  Google Scholar 

  2. Jellinger KA, Bancher C. Neuropathology of Alzheimer’s disease: a critical update. J Neural Transm Suppl 1998, 54: 77–95.

    Article  CAS  PubMed  Google Scholar 

  3. Zetterberg H, Blennow K, Hanse E. Amyloid beta and APP as biomarkers for Alzheimer’s disease. Exp Gerontol 2010, 45: 23–29.

    Article  CAS  PubMed  Google Scholar 

  4. Wisniewski T, Goni F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron 2015, 85: 1162–1176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shi Z, Lu C, Sun X, Wang Q, Chen S, Li Y, et al. Tong Luo Jiu Nao ameliorates Abeta1-40-induced cognitive impairment on adaptive behavior learning by modulating ERK/CaMKII/CREB signaling in the hippocampus. BMC Complement Altern Med 2015, 15: 584.

    Google Scholar 

  6. Kaur N, Dhiman M, Perez-Polo JR, Mantha AK. Ginkgolide B revamps neuroprotective role of apurinic/apyrimidinic endonuclease 1 and mitochondrial oxidative phosphorylation against Abeta -induced neurotoxicity in human neuroblastoma cells. J Neurosci Res 2015, 93: 938–947.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang JF, Qi JS, Qiao JT. Protein kinase C mediates amyloid beta-protein fragment 31–35-induced suppression of hippocampal late-phase long-term potentiation in vivo. Neurobiol Learn Mem 2009, 91: 226–234.

    Article  CAS  PubMed  Google Scholar 

  8. Misiti F, Sampaolese B, Pezzotti M, Marini S, Coletta M, Ceccarelli L, et al. Abeta(31–35) peptide induce apoptosis in PC 12 cells: contrast with Abeta(25–35) peptide and examination of underlying mechanisms. Neurochem Int 2005, 46: 575–583.

    Article  CAS  PubMed  Google Scholar 

  9. Qi JS, Qiao JT. Amyloid beta-protein fragment 31–35 forms ion channels in membrane patches excised from rat hippocampal neurons. Neuroscience 2001, 105: 845–852.

    Article  CAS  PubMed  Google Scholar 

  10. Qi JS, Ye L, Qiao JT. Amyloid beta-protein fragment 31–35 suppresses delayed rectifying potassium channels in membrane patches excised from hippocampal neurons in rats. Synapse 2004, 51: 165–172.

    Article  CAS  PubMed  Google Scholar 

  11. Guo F, Jing W, Ma CG, Wu MN, Zhang JF, Li XY, et al. [Gly(14)]-humanin rescues long-term potentiation from amyloid beta protein-induced impairment in the rat hippocampal CA1 region in vivo. Synapse 2010, 64: 83–91.

    Article  CAS  PubMed  Google Scholar 

  12. Ye L, Qiao JT. Suppressive action produced by beta-amyloid peptide fragment 31–35 on long-term potentiation in rat hippocampus is N-methyl-D-aspartate receptor-independent: it’s offset by (-)huperzine A. Neurosci Lett 1999, 275: 187–190.

    Article  CAS  PubMed  Google Scholar 

  13. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature 2004, 430: 631–639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ferreira ST, Vieira MN, De Felice FG. Soluble protein oligomers as emerging toxins in Alzheimer’s and other amyloid diseases. IUBMB Life 2007, 59: 332–345.

    Article  CAS  PubMed  Google Scholar 

  15. Pan YF, Chen XR, Wu MN, Ma CG, Qi JS. Arginine vasopressin prevents against Abeta(25–35)-induced impairment of spatial learning and memory in rats. Horm Behav 2010, 57: 448–454.

    Article  CAS  PubMed  Google Scholar 

  16. Yan XZ, Qiao JT, Dou Y, Qiao ZD. Beta-amyloid peptide fragment 31–35 induces apoptosis in cultured cortical neurons. Neuroscience 1999, 92: 177–184.

    Article  CAS  PubMed  Google Scholar 

  17. Cheng L, Yin WJ, Zhang JF, Qi JS. Amyloid beta-protein fragments 25–35 and 31–35 potentiate long-term depression in hippocampal CA1 region of rats in vivo. Synapse 2009, 63: 206–214.

    Article  CAS  PubMed  Google Scholar 

  18. Kanski J, Aksenova M, Schoneich C, Butterfield DA. Substitution of isoleucine-31 by helical-breaking proline abolishes oxidative stress and neurotoxic properties of Alzheimer’s amyloid beta-peptide. Free Radic Biol Med 2002, 32: 1205–1211.

    Article  CAS  PubMed  Google Scholar 

  19. Kanski J, Varadarajan S, Aksenova M, Butterfield DA. Role of glycine-33 and methionine-35 in Alzheimer’s amyloid beta-peptide 1–42-associated oxidative stress and neurotoxicity. Biochim Biophys Acta 2002, 1586: 190–198.

    Article  CAS  PubMed  Google Scholar 

  20. Tajima H, Niikura T, Hashimoto Y, Ito Y, Kita Y, Terashita K, et al. Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer’s disease-related insults. Neurosci Lett 2002, 324: 227–231.

    Article  CAS  PubMed  Google Scholar 

  21. Kariya S, Hirano M, Furiya Y, Ueno S. Effect of humanin on decreased ATP levels of human lymphocytes harboring A3243G mutant mitochondrial DNA. Neuropeptides 2005, 39: 97–101.

    Article  CAS  PubMed  Google Scholar 

  22. Chai GS, Duan DX, Ma RH, Shen JY, Li HL, Ma ZW, et al. Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid beta-peptide in rats. Neurosci Bull 2014, 30: 923–935.

    Article  CAS  PubMed  Google Scholar 

  23. Niikura T, Chiba T, Aiso S, Matsuoka M, Nishimoto I. Humanin: after the discovery. Mol Neurobiol 2004, 30: 327-340.

    Article  CAS  PubMed  Google Scholar 

  24. Nishimoto I, Matsuoka M, niikura T. Unravelling the role of Humanin. Trends Mol Med 2004, 10: 102–105.

  25. Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A 2001, 98: 6336–6341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Miao J, Zhang W, Yin R, Liu R, Su C, Lei G, et al. S14G-Humanin ameliorates Abeta25–35-induced behavioral deficits by reducing neuroinflammatory responses and apoptosis in mice. Neuropeptides 2008, 42: 557–567.

    Article  CAS  PubMed  Google Scholar 

  27. Tajima H, Kawasumi M, Chiba T, Yamada M, Yamashita K, Nawa M, et al. A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice. J Neurosci Res 2005, 79: 714–723.

    Article  CAS  PubMed  Google Scholar 

  28. Hashimoto Y, Suzuki H, Aiso S, Niikura T, Nishimoto I, Matsuoka M. Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection. Life Sci 2005, 77: 3092–3104.

    Article  CAS  PubMed  Google Scholar 

  29. Russo M, Russo GL, Daglia M, Kasi PD, Ravi S, Nabavi SF, et al. Understanding genistein in cancer: The “good” and the “bad” effects: A review. Food Chem 2016, 196: 589–600.

    Article  CAS  PubMed  Google Scholar 

  30. Akiyama T, Ishide J, Nakagawa S, Ogaara H, Watanabe S, Itoh N. Genistein, a Specific Inhibitor of Tyrosine-specific Protein Kinases. The Journal of Biological Chemistry 1987, 262: 5592–5595.

    CAS  PubMed  Google Scholar 

  31. Eckert A, Keil U, Marques CA, Bonert A, Frey C, Schussel K, et al. Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease. Biochem Pharmacol 2003, 66: 1627–1634.

    Article  CAS  PubMed  Google Scholar 

  32. Mattson MP. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 1997, 77: 1081–1132.

    CAS  PubMed  Google Scholar 

  33. Jo J, Whitcomb DJ, Olsen KM, Kerrigan TL, Lo SC, Bru-Mercier G, et al. Abeta(1–42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta. Nat Neurosci 2011, 14: 545–547.

    Article  CAS  PubMed  Google Scholar 

  34. Chung CW, Song YH, Kim IK, Yoon WJ, Ryu BR, Jo DG, et al. Proapoptotic effects of tau cleavage product generated by caspase-3. Neurobiol Dis 2001, 8: 162–172.

    Article  CAS  PubMed  Google Scholar 

  35. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. Astrocytes are important mediators of Abeta-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2011, 2: e167. doi:10.1038/cddis.2011.50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kuchipudi SV. The Complex Role of STAT3 in Viral Infections. J Immunol Res 2015, 2015: 272359. doi:10.1155/2015/272359

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (31271201 and 31471080).

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Authors and Affiliations

  1. Department of Physiology, Shanxi Medical University, Taiyuan, 030001, China

    Li Yuan, Qing-Shan Li, Zhao-Jun Wang, Mei-Na Wu, Wei Yang & Jin-Shun Qi

  2. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Xiao-Jie Liu

  3. Department of Physiology, Shaoyang Medical College, Shaoyang, 422000, China

    Wei-Na Han

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  1. Li Yuan
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Correspondence to Jin-Shun Qi.

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Yuan, L., Liu, XJ., Han, WN. et al. [Gly14]-Humanin Protects Against Amyloid β Peptide-Induced Impairment of Spatial Learning and Memory in Rats. Neurosci. Bull. 32, 374–382 (2016). https://doi.org/10.1007/s12264-016-0041-x

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  • DOI: https://doi.org/10.1007/s12264-016-0041-x

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