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Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy


Year of Publication:
Contact PI Name:
Michael G. Agadjanyan
Contact PI Affiliation:
Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, California, USA
Nina Movsesyan, Anahit Ghochikyan, Mikayel Mkrtichyan, Irina Petrushina, Hayk Davtyan, Purevdorj B. Olkhanud, Elizabeth Head, Arya Biragyn, David H. Cribbs
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
Alzheimer's Association
Study Goal and Principal Findings:

The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Aβ antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal this study designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Aβ42 (Aβ1–11) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong antiinflammatory Th2 phenotype. They generated pMDC-3Ab1–11-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3–4 months old. They demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Aβ antibody, which in turn inhibited accumulation of Aβ pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(active)
Therapeutic Agent:
3Ab1–11-PADRE (DNA Epitope Vaccine)
Therapeutic Target:
beta Amyloid Peptide

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
Activated Astrocytes
Activated Microglia
beta Amyloid Deposits
beta Amyloid Load
Tau Pathology
Dense-core/Compact Plaques
Brain-Buffer Insoluble beta Amyloid Peptide 40
Brain-Buffer Insoluble beta Amyloid Peptide 42
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Binding-beta Amyloid Oligomers
beta Amyloid Aggregation
Interleukin 4 (IL-4) Production
Total Tau Protein
Activated Astrocytes
Activated Microglia
Tau Protein
Anti-beta Amyloid IgG Production
Anti-beta Amyloid Peptide 40 Antibody Titers
Anti-beta Amyloid Peptide 42 Antibody Titers
Interferon (IFN) gamma Production
Antibody Target Specificity
T Cell Response
Target Engagement (Reduction beta Amyloid Peptides-Brain)