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 (Aβ) protein and the receptor for advanced glycation endproducts (RAGE) play an important and often deleterious role in the pathogenesis of AD. Aβ 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 Aβ from the periphery into the brain, mediates Aβ induced neurotoxicity, and enhances the release of pro inflammatory cytokines in response to Aβ. In this project, we, therefore, tested the hypothesis (in a model system, the APPSWE-PS1 mouse) that an oral vaccine targeting both RAGE/Aβ would provide a safer and more effective treatment option for AD than vaccination with a standard Aβ1-42 alone treatment. In this study, the oral RAGE/Aβ vaccine was compared to a standard vaccine of Aβ1-42 alone for its immunogenicity, neurotoxicity, capacity to remove Aβ pathology, and cognitive enhancing efficacy. Our results indicate that the RAGE/Aβ vaccine is capable of inducing a greater immunogenic response (increased anti-Aβ1-42 and anti-RAGE antibody titers) in both human peripheral blood mononuclear cells (PBMCs) and immunized Balb-C mice than the response induced by standard Aβ1-42 vaccine alone. The RAGE/Aβ vaccine showed less neurotoxic effects on cultured primary rat cortical neurons than did Aβ1-42 vaccine alone. In addition, the anti-RAGE antibodies produced following administration of the RAGE/Aβ vaccine dose dependently prevented Aβ1-42 induced neurotoxicity. Both the RAGE/Aβ vaccine and the standard Aβ1-42 vaccine were comparable at reducing AP pathology. However, the oral RAGE/AP vaccine was superior compared to the standard Aβ1-42 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.
Department of Pharmacology and Toxicology
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