Epitope analysis following active immunization with tau proteins reveals immunogens implicated in tau pathogenesis

Maj Linda B. Selenica, Hayk Davtyan, Steven B. Housley, Laura J. Blair, Anne Gillies, Bryce A. Nordhues, Bo Zhang, Joseph Liu, Jason E. Gestwicki, Daniel C. Lee, Marcia N. Gordon, Dave Morgan, Chad A. Dickey

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Background: Abnormal tau hyperphosphorylation and its accumulation into intra-neuronal neurofibrillary tangles are linked to neurodegeneration in Alzheimer's disease and similar tauopathies. One strategy to reduce accumulation is through immunization, but the most immunogenic tau epitopes have so far remained unknown. To fill this gap, we immunized mice with recombinant tau to build a map of the most immunogenic tau epitopes. Methods: Non-transgenic and rTg4510 tau transgenic mice aged 5 months were immunized with either human wild-type tau (Wt, 4R0N) or P301L tau (4R0N). Each protein was formulated in Quil A adjuvant. Sera and splenocytes of vaccinated mice were collected to assess the humoral and cellular immune responses to tau. We employed a peptide array assay to identify the most effective epitopes. Brain histology was utilized to measure the effects of vaccination on tau pathology and inflammation. Results: Humoral immune responses following immunization demonstrated robust antibody titers (up to 1:80,000 endpoint titers) to each tau species in both mice models. The number of IFN-γ producing T cells and their proliferation were also increased in splenocytes from immunized mice, indicating an increased cellular immune response, and tau levels and neuroinflammation were both reduced. We identified five immunogenic motifs within either the N-terminal (9-15 and 21-27 amino acids), proline rich (168-174 and 220-228 amino acids), or the C-terminal regions (427-438 amino acids) of the wild-type and P301L tau protein sequence. Conclusions: Our study identifies five previously unknown immunogenic motifs of wild-type and mutated (P301L) tau protein. Immunization with both proteins resulted in reduced tau pathology and neuroinflammation in a tau transgenic model, supporting the efficacy of tau immunotherapy in tauopathy.

Original languageEnglish
Article number152
JournalJournal of Neuroinflammation
Issue number1
StatePublished - Sep 3 2014

Bibliographical note

Funding Information:
This work was supported by NINDS R01 NS073899 and NIRG 13-281227 (Alzheimer’s Association). We would like to thank Prof. Michael G Agadjanyan, PhD, DSc, at the Department of Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USA, for his valuable consulting on the interpretation of the immune responses measured in the sera and splenocytes.

Publisher Copyright:
© 2014 Selenica et al.; licensee BioMed Central Ltd.


  • Active immunization
  • Immunogenicity
  • Neuroinflammation
  • Peripheral response
  • Tau

ASJC Scopus subject areas

  • Neuroscience (all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience


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