Saturday, May 18, 2024
5/18/2024
Abstract Alzheimer's disease is a fatal, progressive brain disease that deteriorates memory and cognitive ability, often starting years before the first symptoms appear. It is the most common form of dementia and the only top 10 cause of death that has no cure, no means of prevention, and no disease-modifying treatments. In this proposal we suggest a combination of novel nanostructure assembly technique based on Flexible Nano Arrays (FNA) and universal non-self vaccine platform MultiTEP for the creation of an efficient AD vaccine targeting Aß dimers. This vaccine would be able to discriminate between pathological and physiological as well as toxic and inert forms of Aß. This becomes especially important in the light of new evidence suggesting the functional importance of Aß in neuronal plasticity and defense against brain infections. Ability to target selectively highly toxic soluble forms of Aß is also important, since generation of antibodies that bind to mostly inert, fibrillar forms of Aß is suboptimal due to the possibility of solubilization of plaques and release of large amounts of toxic soluble Aß oligomers. Also, targeting the fibrillary forms of Aß may lead to increased activation of complement in the regions with vascular amyloid deposits and induce additional adverse effects associated with vascular inflammation. The oligomeric forms of Aß are highly neurotoxic and should be the primary target in AD immunotherapy, yet their structure is not well-defined and is mostly predicted based on the knowledge about the structure of fibrillar Aß. Synthetic oligomeric forms of Aß are transient and heterogeneous in size, therefore we hypothesize that a successful immunotherapy approach for AD needs well-defined antigens. The objective of this proposal is to develop an approach by which a flexible nanoarray will be utilized to assemble dimers of Aß14-23 peptide and conjugate them with the universal and immunogenic MultiTEP platform to generate a novel vaccine targeting dimeric Aß, which is considered to be a seed for the generation of other toxic forms of Aß. The immunogenic efficacy and specificity of the vaccine will be tested in vivo allowing us to optimize the vaccine assembly methodology. We hypothesize that (a) combining conformational B cell epitope/s exposed on Aß14-23 dimers with MultiTEP platform (dAß-MultiTEP) will allow us to generate an effective vaccine, which, after formulation in proprietary Advax/CpG adjuvant, will overcome immunogenicity limitation even in elderly people with immunosenescence; (b) dimer-specific antibodies will not only be therapeutically effective, but also safe, due to the absence of adverse events associated with solubilization of plaques and clearance of monomeric Aß.
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