Acta Neuropathologica

, Volume 127, Issue 6, pp 861–879 | Cite as

Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials

  • Markus Mandler
  • Elvira Valera
  • Edward Rockenstein
  • Harald Weninger
  • Christina Patrick
  • Anthony Adame
  • Radmila Santic
  • Stefanie Meindl
  • Benjamin Vigl
  • Oskar Smrzka
  • Achim Schneeberger
  • Frank Mattner
  • Eliezer MasliahEmail author
Original Paper


Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that α-synuclein (α-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs® (AFF)- that do not elicit an α-syn-specific T cell response. This approach allows for the production of long term, sustained, more specific, non-cross reacting antibodies suitable for the treatment of synucleinopathies, such as Parkinson’s disease (PD). In this context, we screened a large library of peptides that mimic the C-terminus region of α-syn and discovered a novel set of AFF that identified α-syn oligomers. Next, the peptide that elicited the most specific response against α-syn (AFF 1) was selected for immunizing two different transgenic (tg) mouse models of PD and Dementia with Lewy bodies, the PDGF- and the mThy1-α-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized α-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn oligomers in axons and synapses, accompanied by reduced degeneration of TH fibers in the caudo-putamen nucleus and by improvements in motor and memory deficits in both in vivo models. Clearance of α-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies.


Vaccination Parkinson’s disease Immunotherapy Alpha-synuclein AFFITOPE® AFFITOME® 



We thank Andrea Achleitner, Martina-Anna Gschirtz, Michael Hierzer, Beate Pilz, Martina Trefil and Christina Wöss for their contribution in conducting the experiments. This work was funded by the National Institutes of Health (NIH) grants NS044233, AG18440, NS047303, AG022074 and NS057096. In addition, funding was provided by Austrian Science promotion agency (FFG) grants 813335, 817969, 821453 and by the Michael J. Fox foundation for Parkinson's research (MJFF) grant: AFFITOPE® based immunotherapeutic strategies for Parkinson's disease.

Conflict of interest

The authors Markus Mandler, Harald Weninger, Radmila Santic, Stefanie Meindl, Benjamin Vigl, Oskar Smrzka and Achim Schneeberger are employees of AFFiRiS, the company that commercializes the AFFITOPEs® described in the manuscript. The author Frank Mattner is co-founder of AFFiRiS. The authors Elvira Valera, Edward Rockenstein, Christina Patrick, Anthony Adame and Eliezer Masliah declare that they have no conflict of interest.

Supplementary material

401_2014_1256_MOESM1_ESM.docx (64 kb)
Supplementary material 1 (DOCX 64 kb)
401_2014_1256_MOESM2_ESM.pdf (3.5 mb)
Supplementary material 2 (PDF 3633 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Markus Mandler
    • 1
  • Elvira Valera
    • 2
  • Edward Rockenstein
    • 2
  • Harald Weninger
    • 1
  • Christina Patrick
    • 2
  • Anthony Adame
    • 2
  • Radmila Santic
    • 1
  • Stefanie Meindl
    • 1
  • Benjamin Vigl
    • 1
  • Oskar Smrzka
    • 1
  • Achim Schneeberger
    • 1
  • Frank Mattner
    • 1
  • Eliezer Masliah
    • 2
    • 3
    Email author
  1. 1.AFFiRiS AG, Vienna BiocenterViennaAustria
  2. 2.Departments of NeurosciencesUniversity of California, San DiegoLa JollaUSA
  3. 3.Departments of PathologyUniversity of California, San DiegoLa JollaUSA

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