Vaccination of Alzheimer's model mice with adenovirus vector containing quadrivalent foldable Abeta(1-15) reduces Abeta burden and behavioral impairment without Abeta-specific T cell response

Active amyloid beta (Abeta) vaccination has been shown to be effective in clearing cerebral Abeta 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 Abeta(1-42). To avoid this toxicity, previous researchers have been using synthetic truncated Abeta derivatives that promote humoral immunity. In this study, we develop a novel adenovirus vaccine, which can express quadrivalent foldable Abeta(1-15) (4xAbeta(15)) and gene adjuvant GM-CSF in vivo. Importantly, the 4xAbeta(15) sequence includes an Abeta-specific B cell epitope but lacks the reported T cell epitope. The 4xAbeta(15) adenovirus vaccine induces an Abeta-specific IgG1 predominant humoral immune response, and reduces brain Abeta deposition and cognition deficits in Tg2576 mice. Detection of IL-4 and IFN-gamma in restimulated splenocytes shows a significant Th2-polarized immune response. Stimulation of splenocytes with 4xAbeta(15) peptides results in robust proliferative responses, whereas proliferation is absent after stimulation with full-length Abeta, which indicates that the 4xAbeta(15) adenovirus vaccine does not induce Abeta-specific T cellular immune response. Thus, our results raise the possibility that adenovirus vector encoding 4xAbeta(15) would be a promising candidate for future AD vaccination program.