BIOPHYSICS GRADUATE STUDENT SEMINAR<br>Zooming into the Misfolding of the Alzheimer’s Amyloid-ß Peptide
Alzheimer’s disease (AD) is characterized by the misfolding and self-assembly of endogenous amyloidogenic proteins. In the case of AD, this amyloidogenic protein is amyloid-ß (Aß). The aggregation pathway of Aß is sensitive to a variety of conditions and, as a result, gives rise to diverse intermediate states prior to amyloid formation. Recent evidence suggests that these proteinaceous seeds are a potential platform for the propagation of AD via oligomeric species of Aß. The nature and structure of Aß oligomers are poorly understood and seeking high-resolution structural insights of Aß oligomers has been a major challenge to most techniques. Here, we demonstrate the utility of high-resolution 1H MAS NMR spectroscopy in providing atomistic details on a non-frozen, non-isotopically labeled Aß oligomer. Coupled with a variety of biophysical measurements, we show Aß forms a stable, disordered oligomer in parallel with the well-known extended cross-ß-sheet fibers at a physiological pH. Furthermore, we examine the time-course assembly of oligomeric to fibrillar forms of Aß using two-dimensional 1H-15N heteronuclear single-quantum coherence (HSQC) correlation spectra. This combinational approach of using both solution- and solid-state NMR provides atomic-level insight into the misfolding pathway of Aß as it self-associates and transitions from monomer to higher-order aggregated species. By understanding the aggregation of Aß, we aim to advance our understanding of AD pathology and, in turn, we hope that such information may aid in the design of therapeutics to alleviate symptoms of Alzheimer’s disease.