Identification of PrP sequences essential for the interaction between the PrP polymers and Aβ peptide in a yeast-based assay

Alzheimer disease is associated with the accumulation of oligomeric amyloid beta peptide (A beta), accompanied by synaptic dysfunction and neuronal death. Polymeric form of prion protein (PrP), PrPSc, is implicated in transmissible spongiform encephalopathies (TSEs). Recently, it was shown that the monomeric cellular form of PrP (PrPC), located on the neuron surface, binds A beta oligomers (and possibly other beta-rich conformers) via the PrP23-27 and PrP90-110 segments, acting as A beta receptor. On the other hand, PrPSc polymers efficiently bind to A beta monomers and accelerate their oligomerization. To identify specific PrP sequences that are essential for the interaction between PrP polymers and A beta peptide, we have co-expressed A beta and PrP (or its shortened derivatives), fused to different fluorophores, in the yeast cell. Our data show that the 90-110 and 28-89 regions of PrP control the binding of proteinase-resistant PrP polymers to the A beta peptide, whereas the 23-27 segment of PrP is dispensable for this interaction. This indicates that the set of PrP fragments involved in the interaction with A beta depends on PrP conformational state.