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Comparative Study of Inhibition at Multiple Stages of Amyloid-β Self-Assembly Provides Mechanistic Insight

The “amyloid cascade hypothesis,” linking self-assembly of the amyloid-β protein (Aβ) to the pathogenesis of Alzheimer's disease, has led to the emergence of inhibition of Aβ self-assembly as a prime therapeutic strategy for this currently unpreventable and devastating disease. The complexity of Aβ self-assembly, which involves multiple reaction intermediates related by nonlinear and interconnected nucleation and growth mechanisms, provides multiple points for inhibitor intervention. Although a number of small-molecule inhibitors of Aβ self-assembly have been identified, little insight has been garnered concerning the point at which these inhibitors intervene within the Aβ assembly process. In the current study, a julolidine derivative is identified as an inhibitor of Aβ self-assembly. To gain insight into the mechanistic action of this inhibitor, the inhibition of fibril formation from monomeric protein is assessed quantitatively and compared with the inhibition of two distinct mechanisms of growth for soluble Aβ aggregation intermediates. This compound is observed to significantly inhibit soluble aggregate growth by lateral association while having little effect on soluble aggregate elongation via monomer addition. In addition, inhibition of soluble Aβ aggregate association exhibits an IC50 with a somewhat lower stoichiometric ratio than the IC50 determined for inhibition of fibril formation from monomeric Aβ. This quantitative comparison of inhibition within multiple Aβ self-assembly assays suggests that this compound binds the lateral surface of on-pathway intermediates exhibiting a range of sizes to prevent their association with other aggregates, which is required for further assembly into mature fibrils.