X-ray Structure Determination of Complexes of Alzheimer's Amyloid-Beta Peptide with Oligomerization Inhibitors

Alzheimer’s Disease affects millions of patients throughout the world and has widespread, debilitating impacts on patients and their loved ones.1 Current efforts to study the accumulation of the peptide amyloid-beta in interneural spaces and possible mechanisms of amyloid clearance appear promising for the development of future therapies.2 Several small biomolecules with anti-inflammatory and anti-oxidative properties have been shown to impact the aggregation of amyloid-beta and are thus candidates for future drug development, targeting the amyloidogenic, inflammatory, and oxidative stress components of Alzheimer’s pathology.3-6 This study aims to determine the regions on amyloid-beta to which Vitamin B12 binds using X-ray crystallography and diffraction analysis. Literature reviews were conducted to find optimal solution conditions to solubilize amyloid-beta and previously documented interactions between the two molecules. Buffer screens were then carried out and a buffer was selected for subsequent crystallization trials. Crystals of Vitamin B12 and Vitamin B12 with amyloid-beta were generated via hanging drop vapor-diffusion crystallization. Crystals were diffracted using the AMX-17ID-1 beamline of the National Synchrotron Light Source II at Brookhaven National Laboratory, and a structure was determined from one of our crystals of Vitamin B12 and amyloid-beta. Though no amyloid-beta was observed in the unit cell of Vitamin B12 determined from the sample, significant observed heterogeneity in the unit cell warrants further study of these potential complexes. We are currently pursuing the determination of structures from our remaining crystals and the generation of new samples of amyloid-beta and various other small biomolecules demonstrated to impact amyloid-beta’s aggregation.