Efficacy of a therapeutic vaccine using mutated ß-amyloid sensitized dendritic cells in Alzheimer's mice.

ABSTRACT

Despite FDA suspension of Elan's AN-1792 amyloid beta (Aß) vaccine in phase IIb clinical trials, the implications of this study are the guiding principles for contemporary anti-Aß immunotherapy against Alzheimer's disease (AD). AN-1792 showed promising results with regards to Aß clearance and cognitive function improvement, but also exhibited an increased risk of Th1 mediated meningoencephalitis. As such, vaccine development has continued with an emphasis on eliciting a notable anti-Aß antibody titer, while avoiding the unwanted Th1 pro-inflammatory response. Previously, we published the first report of an Aß sensitized dendritic cell vaccine as a therapeutic treatment for AD in BALB/c mice. Our vaccine elicited an anti-Aß titer, with indications that a Th1 response was not present. This study is the first to investigate the efficacy and safety of our dendritic cell vaccine for the prevention of AD in transgenic mouse models (PDAPP) for AD. We also used Immunohistochemistry to characterize the involvement of LXR, ABCA1, and CD45 in order to gain insight into the potential mechanisms through which this vaccine may provide benefit. The results indicate that (1) the use of mutant Aß1-42 sensitized dendritic cell vaccine results in durable antibody production, (2) the vaccine provides significant benefits with regards to cognitive function without the global (Th1) inflammation seen in prior Aß vaccines, (3) histological studies showed an overall decrease in Aß burden, with an increase in LXR, ABCA1, and CD45, and (4) the beneficial results of our DC vaccine may be due to the LXR/ABCA1 pathway. In the future, mutant Aß sensitized dendritic cell vaccines could be an efficacious and safe method for the prevention or treatment of AD that circumvents problems associated with traditional anti-Aß vaccines.