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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2014

Open Access 01-12-2014 | Research

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

Authors: 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

Published in: Journal of Neuroinflammation | Issue 1/2014

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Abstract

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.
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Metadata
Title
Epitope analysis following active immunization with tau proteins reveals immunogens implicated in tau pathogenesis
Authors
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
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2014
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-014-0152-0

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