Credit: © 2010 ACS

The misfolding and aggregation behaviour of the amyloid-β (Aβ) protein — in particular the isoform Aβ42 — is known to be involved in Alzheimer's disease. Early, intermediate, aggregates are now thought to be the most toxic species to cells, rather than fully formed amyloid plaques, but their precise structure remains elusive, rendering the search for aggregation inhibitors difficult. Aggregation enhancers have therefore been suggested as potential alternative drugs, because they reduce the presence of these early intermediates by forming the plaques much more quickly. The lack of structural information has hindered traditional approaches either to design specific inhibitors or to screen molecules for their influence on the aggregation behaviour of Aβ.

Now, Michael Hecht from Princeton University and co-workers have screened potential drugs based solely on their ability to bind to the Aβ peptide1. A small-molecule microarray was prepared by attaching a wide variety of compounds to a glass slide through isocyanate groups. Each slide, which contained thousands of compounds, is probed with an Aβ monomer, fluorescently labelled so the species that bind to it can be detected by fluorescence.

Seventy-nine molecules were identified that bind to the Aβ peptide from this highly sensitive, high-throughput assay, and were subsequently tested for their ability to prevent Aβ42-induced killing of a cell line. Fifteen of these increased the survival of cells incubated with Aβ42 by more than 30%. Further investigations with one of these compounds suggested that it enhanced Aβ42 aggregation. This microarray method shows promise for the identification of therapeutic leads, regardless of their action mechanism.