The effects of a novel oral-vaccine targeted against the RAGE-Abeta complex immunogen on Alzheimer's disease like pathology and cognitive function in APP/PS1 mice

Alzheimer's disease (AD) is an age-related and progressive neurodegenerative illness that causes dementia, marked physical disability, and eventually death. The disease has become a major public health concern given that the elderly population is projected to more than double in the next few decades. Currently, there is no cure for AD and the available treatment options (which are for the most part palliative) do little to modify the progressive neuropathology of the disease. Thus, the need for disease-modifying therapeutics for AD is urgently needed. Immunotherapy (vaccines) aimed at deleterious protein targets in the pathogenesis of AD is an area of research that holds great promise for future disease modifying treatments. However, current AD vaccines utilize harsh adjuvants and rely on injection as a delivery system, which has resulted in unacceptable side effects. The overall goal of this dissertation project was to develop an effective oral vaccine that could be easily tolerated and conveniently administered, thus expanding the available AD treatment options. Substantial evidence suggests that both the amyloid beta (Abeta) protein and the receptor for advanced glycation endproducts (RAGE) play an important and often deleterious role in the pathogenesis of AD. Abeta is the main constituent of the senile plaques that develop in AD and it is also highly toxic to neurons. RAGE facilitates the translocation of Abeta from the periphery into the brain, mediates Abeta induced neurotoxicity, and enhances the release of pro inflammatory cytokines in response to Abeta. In this project, we, therefore, tested the hypothesis (in a model system, the APPSWE-PS1 mouse) that an oral vaccine targeting both RAGE/Abeta would provide a safer and more effective treatment option for AD than vaccination with a standard Abeta1-42 alone treatment. In this study, the oral RAGE/Abeta vaccine was compared to a standard vaccine of Abeta1-42 alone for its immunogenicity, neurotoxicity, capacity to remove Abeta pathology, and cognitive enhancing efficacy. Our results indicate that the RAGE/Abeta vaccine is capable of inducing a greater immunogenic response (increased anti-Abeta1-42 and anti-RAGE antibody titers) in both human peripheral blood mononuclear cells (PBMCs) and immunized Balb-C mice than the response induced by standard Abeta1-42 vaccine alone. The RAGE/Abeta vaccine showed less neurotoxic effects on cultured primary rat cortical neurons than did Abeta1-42 vaccine alone. In addition, the anti-RAGE antibodies produced following administration of the RAGE/Abeta vaccine dose dependently prevented Abeta1-42 induced neurotoxicity. Both the RAGE/Abeta vaccine and the standard Abeta1-42 vaccine were comparable at reducing AP pathology. However, the oral RAGE/AP vaccine was superior compared to the standard Abeta1-42 vaccine at improving cognitive function (both spatial working memory and recognition memory) in the APPSWE-PS1 mouse model of AD. In conclusion, our experimental results support the hypothesis that an oral vaccine that targets both RAGE and AP1-42 will provide a safer, more convenient, and more effective treatment option for AD than vaccination with A[31-42 alone. INDEX WORDS: Alzheimer's disease, RAGE, Apt-42, Vaccine, APPSWE-PS1, Anti-AP, Anti-RAGE, Cognition Enhancement, Neuroprotection, Novel Object Recognition, Radial Arm Water Maze, and Novel Alzheimer's Disease Therapeutics.