RADA likely mimics the adhesive proteins present in the extracellular matrix that contain the RGD tri-peptide motif and modulate cell recognition, adhesion and migration. Indeed, the core RAD motif in the RADA-peptide is similar to the ubiquitous integrin receptor binding site RGD. The PrP protein has been shown to interact with the ECM protein laminin, which contains a RGD domain and has self-assembling properties. Additionally, PrP interacts with the 37 kDa/67 kDa laminin receptor which plays a role in the propagation of Scrapie in vitro. The increase in survival of rodents treated with sulfated glycans after Scrapie infection is likely mediated by disruption of prion/laminin receptor interaction. Interestingly, an inverted RGD domain is found in the rodent PrP protein at the C-terminus that is absent in other species. Our data shows that pre-incubation of RADA with PrPsc brain homogenate prior to inoculation is necessary for its anti-prion activity. Moreover, we show that both PrPc and PrPsc bind RADA and binding can be competitively inhibited with Congo red. The planar dye Congo red has anti-prion activity and is routinely used as an amyloid stain. We also show that Congo red binding competes with RADA for PrP binding and not by binding RADA directly. This suggests that Congo red and RADA share a common binding motif in PrPsc and implies a similar mechanism by which they exert their anti-prion activity. Although the mechanism by which Congo red binds amyloid and PrPsc has not been elucidated, its anti-prion activity may be mediated through stabilization of the PrPsc conformation that then impedes the process required for PrPc conversion. Interestingly, Congo red has a strong self-assembling activity, a property that other symmetric or planar dyes may share, in that they form ribbon-like micellar species that may provide an adhesive structure for binding beta-sheet peptide chains. The symmetrical self-assembled beta-sheet rich RADA-scaffold may provide a complimentary surface for PrPsc binding and consequently uncoupling the process necessary for PrPc to PrPsc conversion. Alternatively, the interaction of PrPsc with RADA may competitively disrupt PrPsc binding to endogenous ECM proteins. This could result in altered clearance of the PrPsc+RADA complex or a distinct extracellular distribution. A change in clearance of PrPsc mediated by RADA binding could result in a reduced PrPsc titer retained in the brain that would account for the delay in prion accumulation at 40 d and the increased survival. Yet, this does not explain the progressive increase in reactive gliosis from the time of inoculation, the increased rate of PrPsc accumulation from 40- to 75 d with a disconnect between the BAY-60-7550 severity of clinical disease and total PrPsc. However, this could be explained by an altered extracellular distribution of the PrPsc-RADA complex. Localization to secondary sites not normally involved in PrPc to PrPsc conversion could act to sequester the PrPsc from it preferred neuronal site.