Reduced pathology and improved behavioral performance in Alzheimer's disease mice vaccinated with HSV amplicons expressing amyloid-beta and interleukin-4.
Immunotherapeutics designed to dissolve existing amyloid plaques or to interrupt amyloid-beta (Abeta) accumulation may be feasible for treatment and/or prevention of Alzheimer's disease (AD). "Shaping" the immune responses elicited against Abeta is requisite toward generating an efficacious and safe outcome; this can be achieved by minimizing the possibility of deleterious inflammatory reactions in the brain as observed in clinical testing of Abeta peptide/adjuvant-based modalities. Herpes simplex virus (HSV)-based amplicons can coexpress multiple antigens and/or immunomodulatory genes due to their large genetic size capacity, thereby facilitating antigen-specific immune response shaping. We have constructed an amplicon (HSV(IE)Abeta(CMV)IL-4) that co-delivers Abeta(1-42) with interleukin-4 (IL-4), a cytokine that promotes the generation of Th2-like T-cell responses, which are favored in the setting of AD immunotherapy. Triple-transgenic AD (3xTg-AD) mice, which progressively develop both amyloid and neurofibrillary tangle pathology, were vaccinated thrice with HSV(IE)Abeta(CMV)IL-4, or a set of control amplicon vectors. Increased Th2-related, Abeta-specific antibodies, improved learning and functioning of memory, and prevention of AD-related amyloid and tau pathological progression were observed significantly more in the HSV(IE)Abeta(CMV)IL-4 vaccinated mice as compared to the other experimental groups. Our study underscores the potential of Abeta immunotherapy for AD and highlights the potency of amplicons in facilitating the immune response modulation to a disease-relevant antigen.
Frazer
Maria E
ME
Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Hughes
Jennifer E
JE
Mastrangelo
Michael A
MA
Tibbens
Jennifer L
JL
Federoff
Howard J
HJ
Bowers
William J
WJ
D000544:Alzheimer Disease / Q000235:genetics* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D007167:Immunotherapy / Q000379:methods; D015847:Interleukin-4 / Q000235:genetics*; D007858:Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D018139:Simplexvirus / Q000235:genetics*
D016229:Amyloid beta-Peptides; D016207:Cytokines; D015847:Interleukin-4