Vaccination of Alzheimer's model mice with adenovirus vector containing quadrivalent foldable Aβ1–15 reduces Aβ burden and behavioral impairment without Aβ-specific T cell response

Active amyloid β (Aβ) vaccination has been shown to be effective in clearing cerebral Aβ and improving cognitive function in mouse models of Alzheimer's disease (AD). The meningoencephalitis observed in AD vaccination trial was likely related to excessive T cell-mediated immunity caused by the immunogen Aβ1–42. To avoid this toxicity, previous researchers have been using synthetic truncated Aβ derivatives that promote humoral immunity. In this study, we develop a novel adenovirus vaccine, which can express quadrivalent foldable Aβ1–15 (4 × Aβ15) and gene adjuvant GM-CSF in vivo. Importantly, the 4 × Aβ15 sequence includes an Aβ-specific B cell epitope but lacks the reported T cell epitope. The 4 × Aβ15 adenovirus vaccine induces an Aβ-specific IgG1 predominant humoral immune response, and reduces brain Aβ deposition and cognition deficits in Tg2576 mice. Detection of IL-4 and IFN-γ in restimulated splenocytes shows a significant Th2-polarized immune response. Stimulation of splenocytes with 4 × Aβ15 peptides results in robust proliferative responses, whereas proliferation is absent after stimulation with full-length Aβ, which indicates that the 4 × Aβ15 adenovirus vaccine does not induce Aβ-specific T cellular immune response. Thus, our results raise the possibility that adenovirus vector encoding 4 × Aβ15 would be a promising candidate for future AD vaccination program.