An improved Forster resonance energy-transfer (FRET) sensor that responses to amyloid beta-peptide (A beta) oligomers was constructed based on the surface-engineered blue and circular permutated yellow fluorescent proteins (BFP and cpYFP), in which A beta-like beta-sheets were embedded. FRET from BFP to cpYFP of the sensor increased by binding to A beta oligomers. Three compounds that affect the A beta aggregation were used as a model for elucidating the screening capabilities of the sensor protein.