Wednesday, January 15, 2025
1/15/2025
Summary The goal of this project is to provide a significant new technology for biomedical research, particularly for researchers studying proteins associated with the progression of Alzheimer's Disease (AD). The majority of efforts to develop therapeutics for AD, most of which have targeted Aβ fibrils, have failed. A growing body of evidence now suggests that oligomeric forms of Aβ, which are intermediates that form during the aggregation process, may be the culprits in disease progression. However, in order to design therapeutics targeting toxic oligomeric species or other altered protein forms, we first require structural information on those species. Here, we propose a new structural method to characterize oligomeric intermediates in aggregation-prone systems, and to test the new methodology on specific amyloid peptides implicated in AD. This work will develop a new structural assay which synergistically combines local and global structural mass spectrometry-based methods. The hydroxyl radical solvent accessibility method reveals local residue-specific structural changes that occur as a function of conformational changes or complex formation, while the native mass spectrometry method reveals global structural information on oligomer size and stoichiometry. These methods will be applied to the study of the amyloid peptides in the familial forms of AD to determine how the oligomeric states of these peptides differ from the wildtype. The new assay will also be used to characterize the interaction between amyloid peptides and the p3 peptide, which is twice as abundant as the more well-studied Aβ, fibrilzes faster than Ab, but can mitigate Ab toxicity. Finally, we will relate these intermediate structural forms to toxicity. These results will be of immense therapeutic value for AD, and will lay the groundwork for future structural investigations of difficult-to-study intermediate forms in a wide range of diseases caused by the aggregation or misfolding of proteins.
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