An Assay for Screening Potential Drug Candidates for Alzheimer's Disease That Act as Chaperones of the Transthyretin and Amyloid-ß Peptides Interaction.

The protein transthyretin (TTR) modulates amyloid-ß (Aß) peptides deposition and processing and this physiological effect is further enhanced by treatment with iododiflunisal (IDIF), a small-molecule compound (SMC) with TTR tetramer stabilization properties, which behaves as chaperone of the complex. This knowledge has prompted us to design and optimize a rapid and simple high-throughput assay that relies on the ability of test compounds to form ternary soluble complexes TTR/Aß/SMC that prevent Aß aggregation. The method uses the shorter Aß(12-28) sequence which is cheaper and simpler to use while retaining the aggregation properties of their parents Aß(1-40) and Aß(1-42). The test is carried out in 96-plate wells that are UV monitored for turbidity during 6 h. Given its reproducibility, we propose that this test can be a powerful tool for efficient screening of SMCs that act as chaperones of the TTR/Aß interaction that may led to potential AD therapies.