Saturday, May 17, 2025
5/17/2025
Structural and Biological Characterization of Diverse Oligomers Derived from Abeta - Project Summary/Abstract: This supplement to AG072587 seeks funding for an under-represented minority (URM) graduate student researcher (GSR) to perform additional studies directed toward Aim 1 of the parent grant and to receive training and mentorship in support of her path to becoming a Ph.D. biomedical research scientist. The parent grant seeks to understand the aggregation of the β-amyloid peptide (Aβ) to form toxic oligomers in Alzheimer’s disease (AD) through the structural, biophysical, and biological profiling of a diverse group of Aβ oligomer models and correlation of these models with biogenic Aβ oligomers. My laboratory has developed an approach to create structurally defined Aβ oligomer models composed of peptide fragments from Aβ constrained into a β-hairpin. We characterize these oligomer models by X-ray crystallography and then introduce chemical crosslinks to create covalently stabilized Aβ oligomer models that mimic the crystallographic oligomers. Studying the crosslinked oligomers then allows detailed correlation between oligomer structure and biophysical and biological properties. Aim 1 of AG072587 seeks to characterize the relationship between Aβ oligomer model structure, assembly, and biology. In this Aim, we characterize how our Aβ oligomer models interact with neurons and other brain cell types to shed light on the relationship between Aβ oligomer structure and cellular events that occur in AD. We also elucidate the relationship between the structures of our Aβ oligomer models and biogenic Aβ oligomers, by generating polyclonal antibodies against the Aβ oligomer models and then examining the immunoreactivity of these antibodies with brain protein extract and brain slices from 5XFAD mice. Aim 2 of AG072587 seeks to discover new Aβ oligomer models, by creating new Aβ β-hairpin peptides that contain more of the Aβ peptide sequence and alternate β-strand alignments. We are creating new crosslinked Aβ oligomer models by identifying key contacts in existing and newly discovered Aβ oligomer models and then engineering in disulfide bonds to stabilize the oligomers. To characterize the structures and oligomerization properties of the new Aβ oligomer models that we generate, we are using X-ray crystallography and a variety of other biophysical experiments. We then characterize biological and immunological properties of these new Aβ oligomer models as outlined in Aim 1. Under the support of the supplement, the URM GSR will develop an approach to allow the creation of mouse polyclonal antibodies against our Aβ oligomer models in order to amplify the impact of Aim 1, which currently only uses rabbit polyclonal antibodies. By expanding Aim 1 to mouse polyclonal antibodies, we will lay the groundwork for creating mouse monoclonal antibodies and their investigation as potential therapies in mouse models for Alzheimer’s disease. The URM GSR plans to investigate this in a subsequent F31 diversity fellowship.
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).