Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY The pathogenesis of Alzheimer’s disease (AD) is characterized by the accumulation and amyloid fibril formation of amyloid-β (Aβ) peptides in the brain. This renewal application proposes to continue our research in the current grant period towards understanding the mechanistic roles of the dynamic and charge-rich N- terminal region of Aβ peptide in Aβ amyloidogenesis. In the new grant period, we propose to expand our systematic N-terminal mutagenesis approaches, and delve into the roles of the N-terminal residues, including those involved in mutagenesis in familial Alzheimer’s disease (FAD), in regulating the microscopic mechanisms of the rate-limiting nucleation process along the aggregation pathway. Importantly, the renewal project will be extended to elucidate the effect of the N-terminus in modulating Aβ oligomerization and fibrillization under the conditions that mimic the in vivo environment. Our central hypothesis is that the flexible and hydrophilic N-terminal region of Aβ is crucial for driving the interactions of the peptide with lipid membrane structures and polyelectrolytes that exist ubiquitously in the brain. We will identify the N-terminal key residues and critical interactions that may play dominating roles in determining Aβ–membrane binding kinetics and thermodynamics, membrane-templated aggregation, Aβ-induced membrane permeabilization and disruption, and Aβ cellular toxicity. An unnatural amino acid p-cyanophenylalanine, which has been successfully employed to identify the local dynamics in Aβ aggregation in the current grant cycle, will be further applied to elucidate the residue-specific dynamics of membrane adsorption and insertion of Aβ peptide. The mechanistic roles of the N-terminus in mediating polyelectrolyte-regulated Aβ aggregation and membrane disruption will also be dissected. The outcome of the proposed research will provide novel insight into the underlying mechanistic function of the dynamic N-terminal region in modulating Aβ aggregation pathway, shedding light on the mechanisms of Aβ amyloidogenesis in vivo and the origin of Aβ pathology in AD. The knowledge from this research may also allow the identification of potential molecular targets, such as the N-terminal key residues and crucial interactions, for design of strategies to manipulate Aβ self- assembly in vivo, which could illuminate the development of new therapeutic treatment for AD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
