MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice.
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.



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.



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.



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.
The Institute for Molecular Medicine, Huntington Beach, CA 92647, United States.
Hayk
H
Davtyan
Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA 92697, United States.
Wesley W
WW
Chen
The Institute for Molecular Medicine, Huntington Beach, CA 92647, United States.
Karen
K
Zagorski
Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, United States; Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, United States.
Joy
J
Davis
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, United States.
Irina
I
Petrushina
The Institute for Molecular Medicine, Huntington Beach, CA 92647, United States.
Konstantin
K
Kazarian
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, United States.
David H
DH
Cribbs
The Institute for Molecular Medicine, Huntington Beach, CA 92647, United States; Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, United States.
Michael G
MG
Agadjanyan
Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA 92697, United States; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, United States; Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, United States. Electronic address: mblurton@uci.edu.
Mathew
M
Blurton-Jones
The Institute for Molecular Medicine, Huntington Beach, CA 92647, United States. Electronic address: aghochikyan@immed.org.
Anahit
A
Ghochikyan
D056704:Adaptive Immunity; D000544:Alzheimer Disease / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy*; D000818:Animals; D000906:Antibodies / Q000097:blood; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D008214:Lymphocytes / Q000276:immunology; D008822:Mice, Transgenic; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016875:tau Proteins / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D000939:Epitopes; D019444:Vaccines, DNA; D016875:tau Proteins
Alzheimer’s diseases; Anti-tau antibody; DNA epitope vaccine; Tau immunotherapy; Transgenic mice