According to amyloid hypothesis the assembly of Abeta peptides into fibrils plays a central role in Alzheimer's disease. Recent experiments suggest that not only Abeta amyloid fibrils, but also Abeta oligomers are potent neurotoxic agents. However, due to complexity of amyloid assembly the associated molecular mechanisms remain poorly understood. The current proposal targets two distinct mechanisms of Alzheimer's amyloidogenesis - the formation of Abeta oligomers and the elongation of preexisting Abeta fibrils by deposition of individual peptides. The main questions of the project are how do these mechanisms of Alzheimer's amyloidogenesis manifest themselves on a single molecule level? Is it possible to develop a combined microscopic description of fibril growth and oligomer assembly, which together represent major events in Abeta amyloidogenesis? What is the molecular basis of anti-aggregation effect produced by certain non-steroidal anti-inflammatory drugs (NSAID)? To answer these questions a molecular model of the pathways of Abeta amyloid assembly will be developed. The proposed work relies on high-end parallel computing and multi-scale molecular modeling. To overcome computational challenges new protein model and new sampling algorithms are employed. Cross-validation strategies to reduce computational artifacts are incorporated in the research plan. The biomedical significance of the proposed work is that the knowledge of molecular mechanisms of Abeta aggregation can be used to devise strategies to control the levels of soluble and fibrillized Abeta peptides. In particular, the project findings will be useful in the design of new NSAID derivatives with stronger anti-aggregation propensity and Abeta imaging efficiency. ? ?
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