Soluble Prion Protein Binds Isolated Low Molecular Weight Amyloid-β Oligomers Causing Cytotoxicity Inhibition

A growing number of observations indicate that soluble amyloid-beta (A beta) oligomers play a major role in Alzheimer's disease. Recent studies strongly suggest that at least some of the neurotoxic effects of these oligomers are mediated by cellular, membrane-anchored prion protein and that A beta neurotoxicity can be inhibited by soluble recombinant prion protein (rPrP) and its fragments. However, the mechanism by which rPrP interacts with A beta oligomers and prevents their toxicity is largely unknown, and studies in this regard are hindered by the large structural heterogeneity of A beta oligomers. To overcome this difficulty, here we used photoinduced cross-linking of unmodified proteins (PICUP) to isolate well-defined oligomers of A beta 42 and characterize these species with regard to their cytotoxicity and interaction with rPrP, as well the mechanism by which rPrP inhibits A beta 42 cytotoxicity. Our data shows that the addition of rPrP to the assembling A beta 42 results in a shift in oligomer size distribution, decreasing the population of toxic tetramers and higher order oligomers and increasing the population of nontoxic (and possibly neuroprotective) monomers. Isolated oligomeric species of A beta 42 are cytotoxic to primary neurons and cause permeation of model lipid bilayers. These toxic effects, which are oligomer size-dependent, can be inhibited by the addition of rPrP, and our data suggest potential mechanisms of this inhibitory action. This insight should help in current efforts to develop PrP-based therapeutics for Alzheimer's disease.