MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice
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Background By the time clinical symptoms of Alzheimer's disease (AD) manifest in patients there is already substantial tau pathology in the brain. Recent evidence also suggests that tau pathology can become self-propagating, further accelerating disease progression. Over the last decade several groups have tested the efficacy of protein-based anti-tau immunotherapeutics in various animal models of tauopathy. Here we report on the immunological and therapeutic potency of the first anti-tau DNA vaccine based on the MultiTEP platform, AV-1980D, in THY-Tau22 transgenic mice.Methods Starting at 3months of age, mice were immunized intramuscularly with AV-1980D vaccine targeting a tau B cell epitope spanning aa2-18 followed by electroporation (EP). Humoral and cellular immune responses in vaccinated animals were analyzed by ELISA and ELISpot, respectively. Neuropathological changes in the brains of experimental and control mice were then analyzed by biochemical (WB and ELISA) and immunohistochemical (IHC) methods at 9months of age.Results EP-mediated AV-1980D vaccinations of THY-Tau22 mice induced activation of Th cells specific to the MultiTEP vaccine platform and triggered robust humoral immunity response specific to tau. Importantly, no activation of potentially harmful autoreactive Th cell responses specific to endogenous tau species was detected. The maximum titers of anti-tau antibodies were reached after two immunizations and remained slightly lower, but steady during five subsequent monthly immunizations. Vaccinations with AV-1980D followed by EP significantly reduced total tau and pS199 and AT180 phosphorylated tau levels in the brains extracts of vaccinated mice, but produced on subtle non-significant effects on other phosphorylated tau species.Conclusions These data demonstrate that MultiTEP-based DNA epitope vaccination targeting the N-terminus of tau is highly immunogenic and therapeutically potent in the THY-Tau22 mouse model of tauopathy and indicate that EP-mediated DNA immunization is an attractive alternative to protein-based adjuvanted vaccines for inducing high concentrations of anti-tau antibodies.
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Active tau immunization reduces tau pathology by targeting single or multiple phospho-epitopes, the amino terminus, full-length normal and mutant tau, or aggregated tau.
“Active tau immunization has been shown to reduce tau pathology by targeting single185, 187, 189–193 or multiple194 phospho-epitopes, the amino terminus195, full-length normal and mutant tau196, 197, or aggregated tau198.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [195]
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Hematological Considerations in Immunotherapy for Alzheimer's Disease
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- Authors
- Davtyan, H., Chen, W. W., Zagorski, K., Davis, J., Petrushina, I., Kazarian, K., Cribbs, D. H., Agadjanyan, M. G., Blurton-Jones, M., & Ghochikyan, A.
- Affiliations
- Institute for Molecular Medicine (US)
- University of California, Irvine (US)
- Corresponding author
- Blurton-Jones, Mathew
- Ghochikyan, Anahit
- ORCID
- Venue
- Vaccine
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 35
- Issue
- 16
- Pages
- 2015-2024
- ISSN
- 0264-410X (ISSN-L)
- PMC
- PMC5395280
- OpenAlex
- W2595931531
- Cited by
- 30
- References
- 54
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 6 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 7 · 2017: 1
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Vaccine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (R01-NS050895, R01-AG020241, U01-AG048310, P50-AG016573, RF1-AG048099)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, DNA vaccine, Alzheimer's disease, tauopathy, electroporation, anti-tau antibodies, tau phosphorylation, immunotherapy, autoreactive T cells
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Epitopes, Brain, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Injections, Intramuscular, Lymphocytes, Mice, Transgenic, Blotting, Western, tau Proteins, Treatment Outcome, Vaccines, DNA, Adaptive Immunity, Enzyme-Linked Immunospot Assay
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