A Strategy for Designing a Molecular Probe for Detection of Beta-Amyloid Oligomers

Aggregation of beta-amyloid (Abeta) into a fibrillar structure is known to be implicated in the pathology of Alzheimer's disease. Development of a robust strategy to detect Abeta oligomeric intermediates, previously identified as significant toxic agents, would be highly beneficial in the screening of drug candidates as well as enhancing our understanding of the molecular basis of Abeta oligomerization. Here, we report the development of a novel molecular probe, PG46, displaying the functional linkage between binding to target species and generation of fluorescence signals. PG46 was found to bind to Abeta oligomers and display an increase in fluorescence. No such event was observed when PG46 was co-incubated with Abeta low molecular weight species or Abeta fibrils. The detection occurred within one hour without any additional sample incubation or preparation steps. The functional linkage could be uncoupled by engineering the connection between domains responsible for binding and signaling. We anticipate that the development of a robust strategy for detection of amyloidogenic oligomers described in this study will be directly relevant to a host of other amyloidogenic proteins.