Advertisement

Molecular Neurobiology

, Volume 56, Issue 4, pp 2353–2361 | Cite as

IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease

  • Huiying Gu
  • Yvonne Kirchhein
  • Timothy Zhu
  • Gang Zhao
  • Hongjun Peng
  • Eileen Du
  • Junyi Liu
  • James A. Mastrianni
  • Martin R. Farlow
  • Richard Dodel
  • Yansheng DuEmail author
Article

Abstract

Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aβ autoantibodies that might be able to treat Alzheimer’s disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Sträussler-Scheinker (GSS)-Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120 days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases.

Keywords

Prion IVIG Amyloid plaque Apoptosis 

Notes

Authors’ Contribution

HG prepared figures and wrote the main manuscript text. YK, TZ, GZ, and HP prepared figures. JM provided the study materials. JL, MF, and RD designed experiments and performed administrative support. ED collected and analyzed data and revised the manuscript. YD designed experiments, performed financial support, and did the final approval of the manuscript. All authors reviewed the manuscript.

Funding

This work was supported by Baudrand Research Foundation.

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

References

  1. 1.
    McKinley MP, Bolton DC, Prusiner SB (1983) A protease-resistant protein is a structural component of the scrapie prion. Cell 35(1):57–62CrossRefGoogle Scholar
  2. 2.
    Prusiner SB (1998) The prion diseases. Brain Pathol 8(3):499–513CrossRefGoogle Scholar
  3. 3.
    Prusiner SB (1991) Molecular biology of prion diseases. Science 252(5012):1515–1522CrossRefGoogle Scholar
  4. 4.
    Yang W, Cook J, Rassbach B, Lemus A, DeArmond SJ, Mastrianni JA (2009) A new transgenic mouse model of Gerstmann-Straussler-Scheinker syndrome caused by the A117V mutation of PRNP. J Neurosci 29(32):10072–10080.  https://doi.org/10.1523/JNEUROSCI.2542-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bugiani O, Giaccone G, Piccardo P, Morbin M, Tagliavini F, Ghetti B (2000) Neuropathology of Gerstmann-Straussler-Scheinker disease. Microsc Res Tech 50(1):10–15.  https://doi.org/10.1002/1097-0029(20000701)50:1<10::AID-JEMT3>3.0.CO;2-6 CrossRefPubMedGoogle Scholar
  6. 6.
    Ghetti B, Piccardo P, Frangione B, Bugiani O, Giaccone G, Young K, Prelli F, Farlow MR et al (1996) Prion protein amyloidosis. Brain Pathol 6(2):127–145CrossRefGoogle Scholar
  7. 7.
    Aguzzi A, Heikenwalder M (2006) Pathogenesis of prion diseases: current status and future outlook. Nat Rev Microbiol 4(10):765–775.  https://doi.org/10.1038/nrmicro1492 CrossRefPubMedGoogle Scholar
  8. 8.
    Cashman NR, Loertscher R, Nalbantoglu J, Shaw I, Kascsak RJ, Bolton DC, Bendheim PE (1990) Cellular isoform of the scrapie agent protein participates in lymphocyte activation. Cell 61(1):185–192CrossRefGoogle Scholar
  9. 9.
    Meiner Z, Halimi M, Polakiewicz RD, Prusiner SB, Gabizon R (1992) Presence of prion protein in peripheral tissues of Libyan Jews with Creutzfeldt-Jakob disease. Neurology 42(7):1355–1360CrossRefGoogle Scholar
  10. 10.
    Bessos H, Drummond O, Prowse C, Turner M, MacGregor I (2001) The release of prion protein from platelets during storage of apheresis platelets. Transfusion 41(1):61–66CrossRefGoogle Scholar
  11. 11.
    Heppner FL, Christ AD, Klein MA, Prinz M, Fried M, Kraehenbuhl JP, Aguzzi A (2001) Transepithelial prion transport by M cells. Nat Med 7(9):976–977.  https://doi.org/10.1038/nm0901-976 CrossRefPubMedGoogle Scholar
  12. 12.
    Aguzzi A, Sigurdson CJ (2004) Antiprion immunotherapy: to suppress or to stimulate? Nat Rev Immunol 4(9):725–736.  https://doi.org/10.1038/nri1437 CrossRefPubMedGoogle Scholar
  13. 13.
    Wisniewski T, Sigurdsson EM (2007) Therapeutic approaches for prion and Alzheimer’s diseases. FEBS J 274(15):3784–3798.  https://doi.org/10.1111/j.1742-4658.2007.05919.x CrossRefPubMedGoogle Scholar
  14. 14.
    Daude N (2004) Prion diseases and the spleen. Viral Immunol 17(3):334–349.  https://doi.org/10.1089/0882824041857139 CrossRefPubMedGoogle Scholar
  15. 15.
    Park CS, Choi YS (2005) How do follicular dendritic cells interact intimately with B cells in the germinal centre? Immunology 114(1):2–10.  https://doi.org/10.1111/j.1365-2567.2004.02075.x CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Glaysher BR, Mabbott NA (2007) Role of the GALT in scrapie agent neuroinvasion from the intestine. J Immunol 178(6):3757–3766CrossRefGoogle Scholar
  17. 17.
    Mabbott NA, Williams A, Farquhar CF, Pasparakis M, Kollias G, Bruce ME (2000) Tumor necrosis factor alpha-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie. J Virol 74(7):3338–3344CrossRefGoogle Scholar
  18. 18.
    Prinz M, Montrasio F, Klein MA, Schwarz P, Priller J, Odermatt B, Pfeffer K, Aguzzi A (2002) Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells. Proc Natl Acad Sci U S A 99(2):919–924.  https://doi.org/10.1073/pnas.022626399 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F, Aguzzi A, Weissmann C (2000) Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288(5469):1257–1259CrossRefGoogle Scholar
  20. 20.
    Mabbott NA, Mackay F, Minns F, Bruce ME (2000) Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. Nat Med 6(7):719–720.  https://doi.org/10.1038/77401 CrossRefPubMedGoogle Scholar
  21. 21.
    Du Y, Dodel R, Hampel H, Buerger K, Lin S, Eastwood B, Bales K, Gao F et al (2001) Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology 57(5):801–805CrossRefGoogle Scholar
  22. 22.
    Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, Jackel S, Wei X et al (2002) Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer’s disease. Ann Neurol 52(2):253–256.  https://doi.org/10.1002/ana.10253 CrossRefPubMedGoogle Scholar
  23. 23.
    Dodel RC, Du Y, Depboylu C, Hampel H, Frolich L, Haag A, Hemmeter U, Paulsen S et al (2004) Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75(10):1472–1474.  https://doi.org/10.1136/jnnp.2003.033399 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Du Y, Wei X, Dodel R, Sommer N, Hampel H, Gao F, Ma Z, Zhao L et al (2003) Human anti-beta-amyloid antibodies block beta-amyloid fibril formation and prevent beta-amyloid-induced neurotoxicity. Brain 126(Pt 9):1935–1939.  https://doi.org/10.1093/brain/awg191 CrossRefPubMedGoogle Scholar
  25. 25.
    Counts SE, Ray B, Mufson EJ, Perez SE, He B, Lahiri DK (2014) Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer’s disease. J Clin Immunol 34(Suppl 1):S80–S85.  https://doi.org/10.1007/s10875-014-0020-9 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lahiri DK, Ray B (2014) Intravenous immunoglobulin treatment preserves and protects primary rat hippocampal neurons and primary human brain cultures against oxidative insults. Curr Alzheimer Res 11(7):645–654CrossRefGoogle Scholar
  27. 27.
    Wei X, Roettger Y, Tan B, He Y, Dodel R, Hampel H, Wei G, Haney J et al (2012) Human anti-prion antibodies block prion peptide fibril formation and neurotoxicity. J Biol Chem 287(16):12858–12866.  https://doi.org/10.1074/jbc.M111.255836 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Dodel R, Balakrishnan K, Keyvani K, Deuster O, Neff F, Andrei-Selmer LC, Roskam S, Stuer C et al (2011) Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer’s disease. J Neurosci 31(15):5847–5854.  https://doi.org/10.1523/JNEUROSCI.4401-10.2011 CrossRefPubMedGoogle Scholar
  29. 29.
    Solforosi L, Criado JR, McGavern DB, Wirz S, Sanchez-Alavez M, Sugama S, DeGiorgio LA, Volpe BT et al (2004) Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303(5663):1514–1516.  https://doi.org/10.1126/science.1094273 CrossRefPubMedGoogle Scholar
  30. 30.
    Roettger Y, Zerr I, Dodel R, Bach JP (2013) Prion peptide uptake in microglial cells—the effect of naturally occurring autoantibodies against prion protein. PLoS One 8(6):e67743.  https://doi.org/10.1371/journal.pone.0067743 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gu H, Zhong Z, Jiang W, Du E, Dodel R, Farlow MR, Zheng W, Du Y (2014) The role of choroid plexus in IVIG-induced beta-amyloid clearance. Neuroscience 270:168–176.  https://doi.org/10.1016/j.neuroscience.2014.04.011 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Cortes CJ, Qin K, Cook J, Solanki A, Mastrianni JA (2012) Rapamycin delays disease onset and prevents PrP plaque deposition in a mouse model of Gerstmann-Straussler-Scheinker disease. J Neurosci 32(36):12396–12405.  https://doi.org/10.1523/JNEUROSCI.6189-11.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gu H, Wei X, Monnot AD, Fontanilla CV, Behl M, Farlow MR, Zheng W, Du Y (2011) Lead exposure increases levels of beta-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice. Neurosci Lett 490(1):16–20.  https://doi.org/10.1016/j.neulet.2010.12.017 CrossRefPubMedGoogle Scholar
  34. 34.
    Tan J, Ma Z, Han L, Du R, Zhao L, Wei X, Hou D, Johnstone BH et al (2005) Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury. Am J Phys Heart Circ Phys 289(5):H2265–H2271.  https://doi.org/10.1152/ajpheart.01106.2004 CrossRefGoogle Scholar
  35. 35.
    Widiapradja A, Vegh V, Lok KZ, Manzanero S, Thundyil J, Gelderblom M, Cheng YL, Pavlovski D et al (2012) Intravenous immunoglobulin protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways. J Neurochem 122(2):321–332.  https://doi.org/10.1111/j.1471-4159.2012.07754.x CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Relkin N (2014) Clinical trials of intravenous immunoglobulin for Alzheimer’s disease. J Clin Immunol 34(Suppl 1):S74–S79.  https://doi.org/10.1007/s10875-014-0041-4 CrossRefPubMedGoogle Scholar
  37. 37.
    Counts SE, Lahiri DK (2014) Overview of immunotherapy in Alzheimer’s disease (AD) and mechanisms of IVIG neuroprotection in preclinical models of AD. Curr Alzheimer Res 11(7):623–625CrossRefGoogle Scholar
  38. 38.
    White AR, Enever P, Tayebi M, Mushens R, Linehan J, Brandner S, Anstee D, Collinge J et al (2003) Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 422(6927):80–83.  https://doi.org/10.1038/nature01457 CrossRefPubMedGoogle Scholar
  39. 39.
    St-Amour I, Bousquet M, Pare I, Drouin-Ouellet J, Cicchetti F, Bazin R, Calon F (2012) Impact of intravenous immunoglobulin on the dopaminergic system and immune response in the acute MPTP mouse model of Parkinson’s disease. J Neuroinflammation 9:234.  https://doi.org/10.1186/1742-2094-9-234 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Huiying Gu
    • 1
  • Yvonne Kirchhein
    • 1
    • 2
  • Timothy Zhu
    • 1
  • Gang Zhao
    • 1
    • 3
  • Hongjun Peng
    • 4
  • Eileen Du
    • 5
  • Junyi Liu
    • 6
  • James A. Mastrianni
    • 7
  • Martin R. Farlow
    • 1
  • Richard Dodel
    • 2
  • Yansheng Du
    • 1
    • 8
    Email author
  1. 1.Department of NeurologyIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of NeurologyPhilipps-University MarburgMarburgGermany
  3. 3.School of Basic Medical SciencesHubei University of Chinese MedicineWuhanPeople’s Republic of China
  4. 4.Department of Pediatrics, Jinling HospitalNanjing University School of MedicineNanjingChina
  5. 5.Department of PsychologyBoston CollegeChestnut HillUSA
  6. 6.Department of Chemical Biology, School of Pharmaceutical SciencesPeking UniversityBeijingChina
  7. 7.Department of NeurologyUniversity of ChicagoChicagoUSA
  8. 8.Department of Anatomy and Histology, School of Basic Medical SciencesTianjin Medical UniversityTianjinChina

Personalised recommendations