Mechanism of Non-Specific Inhibitors of Amyloid Assembly: Interactions of Lacmoid with the Amyloid Beta Peptide

Increasing evidence shows a strong link between the self-assembly of the amyloid beta peptide (Aβ) and the pathogenesis of Alzheimer's disease. Soluble oligomeric Aβ assemblies are thought to be the toxic species causing synaptic and neuronal injury in the patient's brain. Many inhibitors for the oligomerization and/or fibrillation process of neurodegenerative diseases have been reported, yet only little is known about the mechanistic details of these compounds. The present studies concern the interaction of one such inhibitor, lacmoid. We investigated this interaction by a broad biophysical approach revealing similar binding characteristics to Aβ as has been reported for detergents. Furthermore, we show that lacmoid has the ability to inhibit both oligomeric assembly and fibrillation of Aβ. Nuclear magnetic resonance experiments show an overall signal decrease upon addition of lacmoid while the chemical shifts only display small changes. High lacmoid concentration causes a loss of the major part of NMR signals including 1H-15N-HSQC, 1H-15N-TROSY and 1H-13C-HSQC cross-peaks. Circular Dichroism spectroscopy was applied to monitor the kinetic aggregation process of Aβ in presence of lacmoid. Low lacmoid concentrations slow down the conversion from a random coil-like towards a beta-sheet state while at high concentration lacmoid completely prohibits secondary structure changes.Taken together, these findings provide the basis for a simple model which could explain how non-specific interactions with small molecules interfere with amyloid formation. Understanding the mechanistic details is potentially helpful for future drug design of small molecule therapeutics targeting amyloid disorders, such as Alzheimer's disease.