(507e) Inhibition of Amyloid-? Fibril Growth By Enforced Restructuring of the Transition State for Incorporation

The accumulation of the protein fragment amyloid-β (Aβ) outside neurons in the brain is one of the main hallmarks of Alzheimer’s disease. Aβ peptides can aggregate into both soluble oligomers and insoluble fibrils and plaques. In parallel with recent focus on neurotoxic Aβ oligomers and other pathology pathways, the structures and mechanism of Aβ fibril formation are still actively explored. Deeper understanding of the mechanisms of Aβ fibrillization and its response to Alzheimer’s drugs can guide us to more efficient treatments. Bexarotene, an FDA approved drug for cutaneous T cell lymphoma, is one of several small molecules that show promising results in reducing Aβ aggregates in the brain but its mechanism of action remains elusive. The bulk kinetics of fibrillization reveals that bexarotene delays the primary nucleation of fibrils without impacting secondary nucleation and growth. For molecular level insight on how bexarotene operates, we monitor the response of fibril growth to bexarotene by time-resolved in situ atomic force microscopy. The fibril growth rates are indifferent to bexarotene as high as 1 μM, concurrently with bulk fibrillization results. We find that Aβ fibrils generated in presence of bexarotene engage in three surprising behaviors. First, the structural details of the bexarotene fibrils diverge from that of normal Aβ fibrils, suggesting that bexarotene may enforce a distinct fibril polymorph. Second, fibrils generated in the presence of bexarotene kill primary rat hippocampal neurons almost half as efficiently as normal Aβ fibrils. Third, the rate of growth of bexarotene seeds from pure Aβ solutions correlate sublinearly with the peptide concentration and saturation occurs at higher concentrations, in contrast to the linear correlation obtained with normal seeds. We hypothesize that this nonlinear behavior manifests a unique activated complex for growth of the polymorph promoted by bexarotene. The complex delays the transformation of the Aβ monomers into their bulk fibril structure. Urea, known to impair hydrophobic contacts both in the fibril structure and in the activated complex, increases the solubility of fibrils generated in presence of bexarotene, as expected. Surprisingly, urea does not stimulate or suppress the fibril growth rates and ratifies that the activated complex employed by bexarotene seeds is unique. The suggested polymorph transformation driven by bexarotene presents a novel mode of action of drugs that suppress pathological aggregation not only in Alzheimer’s, but also for myriad distinct pathologies that originate with protein condensation.