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Antibodies from a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer’s disease

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Abstract

The neuropathology of Alzheimer’s disease (AD) is characterized by the accumulation of amyloid peptide Aβ in the brain derived from proteolytic cleavage of the amyloid precursor protein (APP). Vaccination of mice with plasmid DNA coding for the human Aβ42 peptide together with low doses of preaggregated peptide induced antibodies with detectable titers after only 2 weeks. One serum was directed against the four aminoterminal amino acids DAEF and differs from previously described ones. Both immune sera and monoclonal antibodies solubilized preformed aggregates of Aβ42 in vitro and recognized amyloid plaques in brain sections of mice transgenic for human APP. Passive immunization of transgenic AD mice caused a significant and rapid reduction in brain amyloid plaques within 24 h. The combined DNA peptide vaccine may prove useful for active immunization with few inoculations and low peptide dose which may prevent the recently described inflammatory reactions in patients. The monoclonal antibodies are applicable for passive immunization studies and may lead to a therapy of AD.

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Abbreviations

AD :

Alzheimer’s disease

:

Amyloid-β

APP :

Amyloid precursor protein

ELISA :

Enzyme-linked immunosorbent assay

GM-CSF :

Granulocyte-macrophage colony-stimulating factor

IL :

Interleukin

SDS :

Sodium dodecyl sulfate

tPA :

Tissue-type plasminogen activator

References

  1. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    CAS  PubMed  Google Scholar 

  2. Esler WP, Wolfe MS (2001) A portrait of Alzheimer secretases-new features and familiar faces. Science 293:1449–1454

    Article  CAS  PubMed  Google Scholar 

  3. LeVine H, 3rd (1993) Thioflavine T interaction with synthetic Alzheimer’s disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci 2:404–410

    CAS  PubMed  Google Scholar 

  4. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    Article  CAS  PubMed  Google Scholar 

  5. Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, Xu S, Eckman C, Younkin S, Price D et al. (1995) Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15:1203–1218

    Article  CAS  PubMed  Google Scholar 

  6. Nicolau C, Greferath R, Balaban TS, Lazarte JE, Hopkins RJ (2002) A liposome-based therapeutic vaccine against beta-amyloid plaques on the pancreas of transgenic NORBA mice. Proc Natl Acad Sci U S A 99:2332–2337

    Article  CAS  PubMed  Google Scholar 

  7. Mohajeri MH, Saini K, Schultz JG, Wollmer MA, Hock C, Nitsch RM (2002) Passive immunization against beta-amyloid peptide protects CNS neurons from increased vulnerability associated with an Alzheimer’s disease-causing mutation. J Biol Chem 14:14

    Google Scholar 

  8. Dodart JC, Bales KR, Paul SM (2003) Immunotherapy for Alzheimer’s disease: will vaccination work? Trends Mol Med 9:85–87

    Article  PubMed  Google Scholar 

  9. Monsonego A, Weiner HL (2003) Immunotherapeutic approaches to Alzheimer’s disease. Science 302:834–838

    Article  CAS  PubMed  Google Scholar 

  10. Frenkel D, Katz O, Solomon B (2000) Immunization against Alzheimer’s beta-amyloid plaques via EFRH phage administration. Proc Natl Acad Sci USA 97:11455–11459

    Article  CAS  PubMed  Google Scholar 

  11. Town T, Tan J, Sansone N, Obregon D, Klein T, Mullan M (2001) Characterization of murine immunoglobulin G antibodies against human amyloid-beta1–42. Neurosci Lett 307:101–104

    Article  CAS  PubMed  Google Scholar 

  12. Solomon B, Koppel R, Frankel D, Hanan-Aharon E (1997) Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci USA 94:4109–4112

    Article  CAS  PubMed  Google Scholar 

  13. O’Nuallain B, Wetzel R (2002) Conformational Abs recognizing a generic amyloid fibril epitope. Proc Natl Acad Sci USA 99:1485–1490

    Article  CAS  PubMed  Google Scholar 

  14. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 98:8850–8855

    Article  CAS  PubMed  Google Scholar 

  15. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264–2267

    Article  CAS  PubMed  Google Scholar 

  16. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM (2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 8:8

    Google Scholar 

  17. Solomon B, Koppel R, Hanan E, Katzav T (1996) Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci USA 93:452–455

    Article  CAS  PubMed  Google Scholar 

  18. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–919

    Article  CAS  PubMed  Google Scholar 

  19. Pirttila T, Kim KS, Mehta PD, Frey H, Wisniewski HM (1994) Soluble amyloid beta-protein in the cerebrospinal fluid from patients with Alzheimer’s disease, vascular dementia and controls. J Neurol Sci 127:90–95

    Article  CAS  PubMed  Google Scholar 

  20. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177

    Article  CAS  PubMed  Google Scholar 

  21. Spooner ET, Desai RV, Mori C, Leverone JF, Lemere CA (2002) The generation and characterization of potentially therapeutic Abeta antibodies in mice: differences according to strain and immunization protocol. Vaccine 21:290–297

    Article  CAS  PubMed  Google Scholar 

  22. Check E (2002) Nerve inflammation halts trial for Alzheimer’s drug. Nature 415:462

    Article  CAS  Google Scholar 

  23. Wolchok JD, Gregor PD, Nordquist LT, Slovin SF, Scher HI (2003) DNA vaccines: an active immunization strategy for prostate cancer. Semin Oncol 30:659–666

    CAS  PubMed  Google Scholar 

  24. Ramshaw IA, Ramsay AJ (2000) The prime-boost strategy: exciting prospects for improved vaccination. Immunol Today 21:163–165

    Article  CAS  PubMed  Google Scholar 

  25. Schultz J, Dollenmaier G, Molling K (2000) Update on antiviral DNA vaccine research (1998–2000). Intervirology 43:197–217

    Article  CAS  PubMed  Google Scholar 

  26. Robinson HL, Montefiori DC, Johnson RP, Kalish ML, Lydy SL, McClure HM (2000) DNA priming and recombinant pox virus boosters for an AIDS vaccine. Dev Biol 104:93–100

    CAS  Google Scholar 

  27. McCluskie MJ, Brazolot Millan CL, Gramzinski RA, Robinson HL, Santoro JC, Fuller JT, Widera G, Haynes JR, Purcell RH, Davis HL (1999) Route and method of delivery of DNA vaccine influence immune responses in mice and non-human primates. Mol Med 5:287–300

    Article  CAS  PubMed  Google Scholar 

  28. Montgomery DL, Shiver JW, Leander KR, Perry HC, Friedman A, Martinez D, Ulmer JB, Donnelly JJ, Liu MA (1993) Heterologous and homologous protection against influenza A by DNA vaccination: optimization of DNA vectors. DNA Cell Biol 12:777–783

    CAS  PubMed  Google Scholar 

  29. Schultz J, Pavlovic J, Strack B, Nawrath M, Moelling K (1999) Long-lasting anti-metastatic efficiency of interleukin 12-encoding plasmid DNA. Hum Gene Ther 10:407–417

    Article  CAS  PubMed  Google Scholar 

  30. Chen CA, Okayama H (1988) Calcium phosphate-mediated gene transfer: a highly efficient transfection system for stably transforming cells with plasmid DNA. Biotechniques 6:632–638

    CAS  PubMed  Google Scholar 

  31. Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, Von Rotz RC, Davey G, Moritz E, Nitsch RM (2002) Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med 8:1270–1275

    Article  CAS  PubMed  Google Scholar 

  32. Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497

    CAS  PubMed  Google Scholar 

  33. Wenschuh H, Volkmer-Engert R, Schmidt M, Schulz M, Schneider-Mergener J, Reineke U (2000) Coherent membrane supports for parallel microsynthesis and screening of bioactive peptides. Biopolymers 55:188–206

    Article  CAS  PubMed  Google Scholar 

  34. Kramer A, Volkmer-Engert R, Malin R, Reineke U, Schneider-Mergener J (1993) Simultaneous synthesis of peptide libraries on single resin and continuous cellulose membrane supports: examples for the identification of protein, metal and DNA binding peptide mixtures. Pept Res 6:314–319

    CAS  PubMed  Google Scholar 

  35. Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549

    Article  CAS  PubMed  Google Scholar 

  36. Moelling K (2000) Viral DNA Vaccines. Intervirology 43:2–10

    Google Scholar 

  37. Weber R, Bossart W, Cone R, Luethy R, Moelling K (2001) Phase I clinical trial with HIV-1 gp160 plasmid vaccine in HIV-1-infected asymptomatic subjects. Eur J Clin Microbiol Infect Dis 20:800–803

    Article  CAS  PubMed  Google Scholar 

  38. Schenk D (2002) Opinion: amyloid-beta immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci 3:824–828

    Article  CAS  PubMed  Google Scholar 

  39. Peretz D, Williamson RA, Kaneko K, Vergara J, Leclerc E, Schmitt-Ulms G, Mehlhorn IR, Legname G, Wormald MR, Rudd PM, Dwek RA, Burton DR, Prusiner SB (2001) Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412:739–743

    Article  CAS  PubMed  Google Scholar 

  40. Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M (2002) Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 298:1379

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Silvia Karer for excellent technical assistance, Ruth Graeferath for help with the thioflavin binding assay, and Jay Tracy for help with the Aβ42 ELISA. One monoclonal antibody was provided by Evotec NeuroScience (Hamburg). This work was supported to R.M.N. by the Kanton Zürich, the NCCR Neural Plasticity and Regeneration, the EU-DIADEM program and the Stammbach Foundation.

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Correspondence to Karin Moelling.

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J.G. Schultz, U. Salzer, and M.H. Mohajeri contributed equally to this manuscript

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Schultz, J.G., Salzer, U., Mohajeri, M.H. et al. Antibodies from a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer’s disease. J Mol Med 82, 706–714 (2004). https://doi.org/10.1007/s00109-004-0570-z

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  • DOI: https://doi.org/10.1007/s00109-004-0570-z

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