Associate Professor University of Central Florida College of Sciences Orlando
The Aβ peptide its various aggregates are potentially implicated in Alzheimer's disease. While the fibrils of different Aβ isomers in aqueous medium have been elucidated, the oligomeric forms Aβ remain elusive, which may contribute to the disease by cell membrane disruption. We report the structure model that describes the membrane-embedded structure of Aβ1-42 and the peptide-lipid interactions. Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), solid state nuclear magnetic resonance (ssNMR) and molecular dynamics approaches are combined to achieve a high-resolution structure model to study the Aβ1-42 oligomer in lipid bilayer environments. Our FTIR data delineate the conformation transition of Aβ1-42 to a stable β-sheet structure. SsNMR characterizes the structure of the peptide, with insertion interactions with the lipid in the vesicles. Based on the ssNMR restraints, MD simulations establish a structure model that shows Aβ1-42 octamers in a novel shushi-roll fold of in-register cross-β motif with lipid-filled internal cavity. Combined, our studies provide new structural insights to advance our understanding of Aβ neurotoxicity, which may be exploited for structure-based drug design.
Although Aβ's implications in Alzheimer's disease is widely accepted, a mechanistic understanding of its neurotoxicity is still lacking, especially regarding the interaction of Aβ oligomer with cell membrane. Our results provide new knowledge to bridge this gap, which may facilitate the structure-guided drug design against Alzheimer's disease
Yes, it will be interesting to anyone working in Aβ or Alzheimer's disease field. We could have open question session and discuss potential collaborations.
Researchers in the Alzheimer's disease research and drug discovery.
Learning Objectives:
Upon completion, participants will be able to see how Aβ1–42 peptide insert lipid bilayers and punctuates holes in the membrane, which explains how Aβ disrupts cellular function.
Upon completion, participant will be able to see how different biophysical techniques can work in synergic to reveal critical structure knowledge that may pave the foundation for drug discovery.
Upon completion, participant will be able to appreciate the interaction of Aβ with membrane also depends on the lipid composition.
