Reduced Pathology and Improved Behavioral Performance in Alzheimer's Disease Mice Vaccinated With HSV Amplicons Expressing Amyloid-β and Interleukin-4

Abstract

Immunotherapeutics designed to dissolve existing amyloid plaques or to interrupt amyloid-β (Aβ) accumulation may be feasible for treatment and/or prevention of Alzheimer's disease (AD). "Shaping" the immune responses elicited against Aβ 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 Aβ 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_IEAβ_CMVIL-4) that co-delivers Aβ_1-42with 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_IEAβ_CMVIL-4, or a set of control amplicon vectors. Increased Th2-related, Aβ-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_IEAβ_CMVIL-4 vaccinated mice as compared to the other experimental groups. Our study underscores the potential of Aβ immunotherapy for AD and highlights the potency of amplicons in facilitating the immune response modulation to a disease-relevant antigen.