Congo red and thioflavin-T analogs detect A beta oligomers

Several small molecule ligands for amyloid-beta (A beta) fibrils deposited in brain have been developed to facilitate radiological diagnosis of Alzheimer's disease (AD). Recently, the build-up of A beta oligomers (A beta O) in brain has been recognized as an additional hallmark of AD and may play a more significant role in early stages. Evidence suggests that quantitative assessment of A beta O would provide a more accurate index of therapeutic effect of drug trials. Therefore, there is an urgent need to develop methods for efficient identification as well as structural analysis of A beta O. We found that some well established amyloid ligands, analogs of Congo red and thioflavin-T (ThT), bind A beta O with high affinity and detect A beta O in vitro and in vivo. Binding studies revealed the presence of binding sites for Congo red- and thioflavin-T-analogs on A beta O. Furthermore, these ligands can be used for imaging intracellular A beta O in living cells and animals and as positive contrast agent for ultrastructural imaging of A beta O, two applications useful for structural analysis of A beta O in cells. We propose that by improving the binding affinity of current ligands, in vivo imaging of A beta O is feasible by a 'signal subtraction' procedure. This approach may facilitate the identification of individuals with early AD.